TREM2 modulators

Abstract

The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 ("TREM2"). The invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.

Description

[0001] TREM2 modulators

[0002] Technical field

[0003] The present invention relates to compounds useful for modulating Triggering Receptor Expressed on Myeloid Cells-2 (“TREM2”). The invention also relates to the compounds for use in treatment of conditions related to loss of function of TREM2, such as neurodegenerative diseases, and to pharmaceutical compositions comprising the compounds.

[0004] Background

[0005] Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor belonging to the immunoglobulin superfamily and is encoded by the TREM2 gene, which maps to human chromosome 6p21. TREM2 consists of an extracellular part that includes a single immunoglobulin domain and a short ectodomain, a single transmembrane helix and a short cytosolic tail (Colonna, M. et al. (2016))).

[0006] Insight to the role of TREM2 is provided by its restricted expression pattern. It is expressed exclusively on myeloid lineage cells, such as macrophages, microglia, dendritic cells and osteoclasts. It plays a role in tissue maintenance, as a sensor of pathology and inducer of innate immune signalling in specific tissues. In the brain TREM2 is exclusively expressed in microglia and is functionally required e.g. in phagocytosis of cellular debris, but has also been assigned roles in restricting inflammation as well as promoting cell survival (Deczkowska, A. et al. (2020)).

[0007] TREM2 has a wide range of ligands such as bacterial anionic molecules / endotoxins, phospholipids incl phosphatidylserine, lipoproteins and apolipoproteins incl ApoE, as well as oligomeric Ap (Hammond, T. R. (2019)).

[0008] Signaling via TREM2 is well described through co-receptor DAP12. The adaptor molecule DAP 12 is expressed as a homodimer at the surface of a variety of cells participating in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells. After ligation of TREM2, ITAM (immunoreceptor tyrosine-based activation motif) tyrosine phosphorylation of DAP12 by SRC-family kinases drive the recruitment and activation of the Syk kinase and / or ZAP70 kinase. Downstream of TREM2 / DAP12 / Syk several signaling pathways have been described involved in cell survival, cell activation and differentiation, and in the control of the actin cytoskeleton.

[0009] Proteolytic cleavage of the ectodomain of TREM2 by metalloproteinases, including ADAM 10 and ADAM 17 and possibly matrix metalloproteinases, leads to the shedding of soluble TREM2 (sTREM2), which can be detected in human cerebrospinal fluid (CSF). sTREM2 has been suggested as a potential biomarker for microglia activity in early-stage Alzheimer’s disease (Suarez-Calvet, M. et al. (2016)).

[0010] Deficiency of either TREM2 or DAP12 leads to a blunted microglial response to pathological agents. The impact of TREM2-deficiency in vitro has been shown in the context of stimulation with typical TLR ligands, such as LPS. Loss-of-function genetic variants of TREM2 are associated with neurodegenerative diseases and supports a central role of microglial function in disease pathogenesis. Homozygous loss-of- function TREM2 variants cause Nasu-Hakola disease (Yamazaki, K. et al. (2015); Paloneva BM, J. et al. (2001); Ulrich J.D. et al. (2017)), whereas heterozygous loss-of- function TREM2 variants are associated with an increased risk for several neurological and neurodegenerative disorders such as Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), Parkinson's disease, FTLD-like syndrome, and Amyotrophic lateral sclerosis (ALS). The most prevalent mutation associated with AD is the loss-of-function mutation R47H, which has been shown to abrogate ligand binding and phagocytosis (Atagi, Y. et al. (2015); Kleinberger, G. et al (2014)).

[0011] Neurodegenerative disorders that may be treated by modulation of TREM2 activity and / or signaling include, but is not limited to, Alzheimer's disease (AD), Frontotemporal lobar degeneration (FTLD), FTLD-like syndrome, Parkinson's disease, Huntington disease, Nasu-Hakola disease (also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy), Multiple sclerosis (MS), Guillain- Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie- Tooth disease andAmyotrophic lateral sclerosis (ALS). Thus, there is a high and unmet medical need for TREM2 modulators to address these indications.

[0012] Summary

[0013] The present invention relates to compounds that modulates TREM2. In one aspect, the present invention relates to a compound of Formula (I),

[0014] Formula (I) wherein

[0015] X1is N or C(R6);

[0016] R6is H or F

[0017] X2is N or C(H);

[0018] R1is C1-6 alkyl optionally substituted with one or more, identical or different, R13, or a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6-membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic;

[0019] R13is C1-3 alkoxy;

[0020] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen;

[0021] R2is of Formula (II):

[0022] Formula (II)

[0023] X3is O or N(R4);

[0024] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0025] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;

[0026] R7is individually H, F or CH3, and n is 0, 1 or 2; or n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s); R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0027] In one aspect, the present invention relates a compound of Formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with loss-of-function of TREM2, such as a neurodegenerative disease.

[0028] Definitions

[0029] As used herein, the singular forms “a,” “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0030] The terms “approximately” and “about” as referred herein are synonymous. In some embodiments, “about” refer to the recited amount, value, or duration ±20%, ±10%, ± 5%, ± 4%, ±3%, ±2%, ±1 %, or ± 0.5%.

[0031] The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified.

[0032] The terms “C1-3 alkyl”, “C1-5 alkyl” and “C1-6 alkyl” as used herein refer to a straight or branched hydrocarbon chains containing from 1 to 3, 1 to 5, and 1 to 6 carbon atoms, respectively. Representative examples of C1-3 alkyl, C1-5 alkyl and C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tertbutyl, pentyl and hexyl.

[0033] The term “C3-6 cycloalkyl” as used herein refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 6 carbon atoms. Representative examples of C3- 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] The term “C1-3 alkoxy” and “C1-6 alkoxy” as used herein refer to -OR#, wherein R#represents a C1-3 alkyl and C1-6 alkyl group, respectively, as defined herein. Representative examples of C1-3 alkoxy and C1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.

[0035] The term “halogen” as used herein refers to -F, -Cl, -Br, or -I. In some embodiments, the halogen is F. In some embodiments, the halogen is Cl.

[0036] The term “halo” as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein. The halogen is independently selected at each occurrence. For example, the term “C1-6 haloalkyl” refers to a C1-6 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.

[0037] Representative examples of C1-6 haloalkyl include, but are not limited to, -CH2F, -CHF2, -CF3, -CHFCI, -CH2CF3, -CFHCF3, -CF2CF3, -CH(CF3)2, -CF(CHF2)2, and - CH(CH2F)(CF3). Further, the term “C1-6 haloalkoxy” for example refers to a C1-6 alkoxy as defined herein, wherein one or more hydrogen atoms are substituted with a halogen. Representative examples of C1-6 haloalkoxy include, but are not limited to, - OCH2F, -OCHF2, -OCF3, -OCHFCI, -OCH2CF3, -OCFHCF3, -OCF2CF3, -OCH(CF3)2, - OCF(CHF2)2, and -OCH(CH2F)(CF3).

[0038] The term “CN” is used herein to indicate a cyano group

[0039] The term “5-membered heteroaryl” or “6-membered heteroaryl” as used herein refers to a 5 or 6-membered carbon ring with two or three double bonds containing one ring heteroatom selected from N, S, and O and optionally one or two further ring N atoms instead of the one or more ring carbon atom(s). Representative examples of a 5- membered heteroaryl include, but are not limited to, furyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and oxazolyl. Representative examples of a 6- membered heteroaryl include, but are not limited to, pyridyl, pyrimidyl, pyrazyl, and pyridazyl.

[0040] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 4 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0041] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl” or “heteroaralkoxy” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” in the context of “heteroaryl” particularly includes, but is not limited to, nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin- 3(4H)-one. A heteroaryl group may be monocyclic or bicyclic. A heteroaryl ring may include one or more oxo (=0) or thioxo (=S) substituent. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0042] As described herein, compounds of the present invention may contain “substituted” moieties. In general, the term “substituted” means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at one or more substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position, i.e. the substituent may be individually / independently selected from a group of substituents. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds.

[0043] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0044] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0045] Detailed description

[0046] In one aspect, the present invention relates to a compound of Formula (I),

[0047] Formula (I) wherein

[0048] X1is N or C(R6);

[0049] R6is H or F

[0050] X2is N or C(H);

[0051] R1is C1-6 alkyl optionally substituted with one or more, identical or different, R13, or a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6-membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic;

[0052] R13is C1-3 alkoxy;

[0053] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen;

[0054] R2is of Formula (II):

[0055] Formula (II)

[0056] X3is O or N(R4);

[0057] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0058] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;

[0059] R7is individually H, F or CH3, and n is 0, 1 or 2; or n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s);

[0060] R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0061] In some embodiments, X1is N. In some embodiments, X1is C(R6), and R6is selected from the group consisting of H, F, -OC1-3 alkyl, and -C(0)Ci-3 alkyl. In some embodiments, X1is C(H).

[0062] In some embodiments, X2is N. In some embodiments, X2is C(H).

[0063] In some embodiments, at least one of X1and X2is N. In some embodiments, X1is N and X2is N; X1is N and X2is C(H); or X1is C(H) and X2is N. In some embodiments, X1is N and X2is N. In some embodiments, X1is N and X2is C(H). In some embodiments, X1is C(H) and X2is N.

[0064] In one aspect, the present invention relates to a compound of Formula (I),

[0065] Formula (I) wherein

[0066] X1is N or C(R6);

[0067] R6is H or F

[0068] X2is N or C(H); and at least one X1and X2is N;

[0069] R1is a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-membered heteroaryl;

[0070] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0; and halogen;

[0071] R2is of Formula (V):

[0072] Formula (V)

[0073] X3is O or N(R4);

[0074] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0075] R5is pyrazolyl optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;

[0076] R7is individually H, F or CH3, and n is 0, 1 or 2;

[0077] R3is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, R1is a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6- membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic.

[0079] In some embodiments, R1a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; and

[0080] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen.

[0081] In some embodiments, R1is phenyl substituted with one or more, identical or different, R14.

[0082] In some embodiments, R1is phenyl. In some embodiments, R1is phenyl substituted with C1-3 alkyl. In some embodiments, R1is phenyl substituted with -CH3. In some embodiments, R1is . In some embodiments, R1is phenyl substituted with

[0083] CN. In some embodiments, R1is . In some embodiments, R1is phenyl substituted with C1-3 alkoxy. In some embodiments, R1is phenyl substituted with -

[0084] OCH3. In some embodiments, R1is . In some embodiments, R1is . , . In some embodiments, R1is phenyl substituted with CN and -CH3. In some embodiments, R1is phenyl substituted with CN and cyclopropyl.

[0085] In some embodiments, R1is a 6-membered heteroaryl optionally substituted with one or more, identical or different, R14. In some embodiments, R1is a 6-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen. In some embodiments, R1 is a 6-membered heteroaryl optionally substituted with C1-3 alkyl. In some embodiments, R1is a 6-membered heteroaryl substituted with -CH3. In some embodiments, the 6-membered heteroaryl is pyridinyl. In some embodiments, R1is pyridinyl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen. In some embodiments, R1is a 6-membered heteroaryl optionally substituted with -OC1-3 alkyl. In some embodiments, R1is a 6-membered heteroaryl substituted with -OCH3. In some embodiments, R1is a 6-membered heteroaryl optionally substituted with halogen. In some embodiments, R1is a 6-membered heteroaryl substituted with Cl.

[0086] In some embodiments, R1is pyridinyl. In some embodiments, the pyridinyl is 2- pyridinyl. In some embodiments, the pyridinyl is 3-pyridinyl. In some embodiments, the pyridinyl is 4-pyridinyl. In some embodiments, R1is In some embodiments,

[0087] R1is . In some embodiments, R1is In some embodiments, R1is pyridinyl substituted with C1-3 alkyl. In some embodiments, R1is pyridinyl substituted with -CH3. In some embodiments,

[0088] In some embodiments, R1is pyridinyl substituted with C1-3 alkoxy.

[0089] In some embodiments, R1is pyridinyl substituted with -OCHs.ln some embodiments, R1is pyridinyl substituted with halogen.

[0090] In some embodiments, R1is pyridinyl substituted with Cl.

[0091] In some embodiments, R1is a 5-membered heteroaryl optionally substituted with one or more, identical or different, R14. In some embodiments, R1is a 5-membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen. In some embodiments, R1is a 5-membered heteroaryl optionally substituted with C1-3 alkyl. In some embodiments, R1is a 5-membered heteroaryl substituted with -CH3. In some embodiments, the 5-membered heteroaryl is pyrazolyl. In some embodiments, R1is pyrazolyl optionally substituted with C1-3 alkyl. In some embodiments, R1is pyrazolyl substituted with -CH3. In some embodiments, some embodiments, some embodiments, the

[0092] 5-membered heteroaryl is oxazolyl. In some embodiments, R1is oxazolyl optionally substituted with C1-3 alkyl. In some embodiments, R1is oxazolyl. In some embodiments, R1is . In some embodiments, the 5-membered heteroaryl is isoxazolyl. In some embodiments, R1is isoxazolyl optionally substituted with C1-3 alkyl.

[0093] In some embodiments, R1is isoxazolyl. In some embodiments, R1is

[0094] In some embodiments, R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen. I.e., in some embodiments, R14is individually selected from the group consisting of:

[0095] • C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens;

[0096] • C3-5 cycloalkyl;

[0097] • C1-3 alkoxy;

[0098] • CN;

[0099] • =0, and

[0100] • halogen.

[0101] In some embodiments, R14is C1-3 alkyl. In some embodiments, R14is CH3. In some embodiments, R14is C1-3 alkyl optionally substituted with =0. In some embodiments, R14is -C(0)CH3. In some embodiment, R14is C1-3 alkyl optionally substituted with =0 and / or -N(CH3)2. In some embodiments, R14is C1-3 alkyl optionally substituted with 1 to 3 halogens. In some embodiments, R14is C3-5 cycloalkyl. In some embodiments, R14is cyclopropyl. In some embodiments, R14is C1-3 alkoxy. In some embodiments, R14is - OCH3. In some embodiments, R14is CN. In some embodiments, R14is =0. In some embodiments, R14is halogen. In some embodiments, R14is Cl. In some embodiments, R13is OCH3. In some embodiments, R1is -(CF^OCHs. In some embodiments, R1is -(CFkhOCHs.

[0102] In some embodiments, R2is of Formula (Ila):

[0103] Formula (Ila) wherein X3, R5, R7, and n are as defined in classes and subclasses herein, both singly and in combination.

[0104] In some embodiments, R2is of Formula (lib):

[0105] Formula (lib) wherein X3, R5, R7, and n are as defined in classes and subclasses herein, both singly and in combination.

[0106] In some embodiments, X3is O. In some embodiments, R2is of Formula (III):

[0107] Formula (III) wherein R5, R7, and n are as defined in classes and subclasses herein, both singly and in combination.

[0108] In some embodiments, X3is N(R4). In some embodiments, R2is of Formula (IV):

[0109] Formula (IV) wherein R4, R5, R7, and n are as defined in classes and subclasses herein, both singly and in combination.

[0110] In some embodiments, n is 0. In some embodiments, n is 1.

[0111] In some embodiments, R2is of Formula (V):

[0112] Formula (V) wherein

[0113] X3is O or N(R4);

[0114] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl; and

[0115] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl.

[0116] In some embodiments, R2is of Formula (Va):

[0117] Formula (Va) wherein X3and R5are as defined in classes and subclasses herein, both singly and in combination. In some embodiments, R2is of Formula (Vb):

[0118] Formula (Vb) wherein X3and R5are as defined in classes and subclasses herein, both singly and in combination. In some embodiments, R2is of Formula (VI):

[0119] Formula (VI) wherein

[0120] X3is O or N(R4);

[0121] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0122] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl; and

[0123] R7is H, F or CH3.

[0124] In some embodiments, R2is of Formula (Via):

[0125] Formula (Via) wherein X3, R5, and R7are as defined in classes and subclasses herein, both singly and in combination.

[0126] In some embodiments, R2is of Formula (Vlb):

[0127] Formula (Vlb) wherein X3, R5, and R7are as defined in classes and subclasses herein, both singly and in combination.

[0128] In some embodiments, R2is of Formula (Vic):

[0129] Formula (Vic) wherein X3, R5, and R7are as defined in classes and subclasses herein, both singly and in combination.

[0130] In some embodiments, R2is of Formula (Vid):

[0131] Formula (Vid) wherein X3, R5, and R7are as defined in classes and subclasses herein, both singly and in combination.

[0132] In some embodiments, X3is O. In some embodiments, X3is N(R4) and R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl. In some embodiments, X3is N(R4) and R4is C1-3 alkyl. In some embodiments, R4is ethyl.

[0133] In some embodiments, R7is individually H, F or CH3, and n is 0, 1 or 2. In some embodiments, R7is individually F or CH3, and n is 0, 1 or 2. In some embodiments, R7is H. In some embodiments, R7is CH3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s).

[0134] In some embodiments, R5is pyrazolyl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl. In some embodiments, R5is of Formula (XI): Formula (XI) wherein

[0135] R8is C1-3 alkyl, C3-6 cycloalkyl or H.

[0136] In some embodiments, R5is of Formula (XII):

[0137] Formula (XII) wherein

[0138] R8is C1-3 alkyl, C3-6 cycloalkyl or H.

[0139] In some embodiments, R8is C1-6 alkyl In some embodiments, R8is C1-3 alkyl. In some embodiments, R8is -CH3. In some embodiments, R8is C3-6 cycloalkyl. In some embodiments, R8is cyclopropyl.

[0140] In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is H, and R5is 1-methyl-1 H-pyrazol-4-yl)piperazin-1-yl. In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is H, and R5is 1-cyclopropyl- 1 H-pyrazol-4-yl)piperazin-1-yl. In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is CH3, and R5is 1-methyl-1 H-pyrazol-4- yl)piperazin-1-yl. In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is CH3, and R5is 1-cyclopropyl-1 H-pyrazol-4-yl)piperazin-1-yl. In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is N(CH2CH3), R7is H, and R5is 1-methyl-1 H-pyrazol-4-yl)piperazin-1-yl. In some embodiments, R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is N(CH2CH3), R7is H, and R5is 1-cyclopropyl-1 H-pyrazol-4-yl)piperazin-1-yl.

[0141] In some embodiments, R3is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN. In some embodiments, R3is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1- 3 haloalkyl, C1-3 alkoxy, and CN. In some embodiments, R3is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN. In some embodiments, R3is of Formula (XIII):

[0142] Formula (XIII) wherein

[0143] R9is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[0144] R10is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; R11is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; and R12is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN.

[0145] In some embodiments, R3is phenyl substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, with the proviso that the phenyl is substituted with a halogen or CN in the para position. I.e., in some embodiments, R3is of Formula (XIII) wherein R11is halogen or CN.

[0146] In some embodiments, R9is H. In some embodiments, R9is halogen, such as F or Cl. In some embodiments, R9is C1-3 alkyl, such as -CH3. In some embodiments, R9is CN. In some embodiments, R10is H. In some embodiments, R10is halogen, such as F. In some embodiments, R11is halogen, such as F or Cl. In some embodiments, R11is C1-3 alkyl, such as -CH3. In some embodiments, R11is C1-3 haloalkyl, such as -CF3. In some embodiments, R11is C1-3 haloalkyl. In some embodiments, R11is CN. In some embodiments, R11is C1-3 alkoxy. In some embodiments, R11is -OCH3. In some embodiments, R12is H. In some embodiments, R12is halogen, such as F. In some embodiments, R10is H and R12is H. In some embodiments, R3is selected from the group consisting of: selected from the group consisting of:

[0147] In some embodiments, some embodiments, some embodiments,

[0148] In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)-N-phenylpyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2- fluorophenyl)-N-(2-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-N-(3- methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-N-(4-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)-N-(o-tolyl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2- fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(pyridin-2-yl)pyrimidine-4- carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-3-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)-N-(pyridin-4-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4- chloro-2-fluorophenyl)-N-(isoxazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H- pyrazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4- chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(oxazol-2- yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol- 4-yl)morpholino)-N-(1-methyl-1 H-pyrazol-5-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4- chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-3-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-N-(4- cyanophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2- (4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(3- methylpyridin-4-yl)pyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4-chloro-2-fluorophenyl)-6-(2-(1- methyl-1 H-pyrazol-4-yl)morpholino)-N-phenylisonicotinamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 6-(4-chloro-2- fluorophenyl)-4-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-phenylpicolinamide, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is 2-(4- chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4-yl)piperazin-1-yl)-N- phenylpyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. pharmaceutically acceptable salt thereof.

[0149] In one aspect, the present invention relates to a compound is selected from the group consisting of: 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpyrimidine-4-carboxamide;

[0150] 2-(4-chloro-2-fluorophenyl)-N-(2-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0151] 2-(4-chloro-2-fluorophenyl)-N-(3-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0152] 2-(4-chloro-2-fluorophenyl)-N-(4-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0153] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(o- tolyl)pyrimidine-4-carboxamide;

[0154] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(pyridin-2- yl)pyrimidine-4-carboxamide;

[0155] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(pyridin-3- yl)pyrimidine-4-carboxamide;

[0156] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(pyridin-4- yl)pyrimidine-4-carboxamide;

[0157] 2-(4-chloro-2-fluorophenyl)-N-(isoxazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0158] 2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide; 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(oxazol-2- yl)pyrimidine-4-carboxamide;

[0159] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(1-methyl- 1 H-pyrazol-5-yl)pyrimidine-4-carboxamide;

[0160] 2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-3-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0161] 2-(4-chloro-2-fluorophenyl)-N-(4-cyanophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0162] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(3- methylpyridin-4-yl)pyrimidine-4-carboxamide;

[0163] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylisonicotinamide;

[0164] 6-(4-chloro-2-fluorophenyl)-4-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpicolinamide; and 2-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4-yl)piperazin-1-yl)-N- phenylpyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0165] Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H- imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H- pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Tautomeric forms can also include methyltropic tautomers, which result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a methyl group.

[0166] Compounds of the invention also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. In some embodiments, the compounds of the invention include one or more isotopes of atoms in an amount greater than the natural abundance of the isotope. For example, isotopes of hydrogen include tritium and deuterium. In some embodiments, a compound of the invention includes at least one deuterium atom in an amount that is greater than the natural abundance of deuterium (e.g., the compound is enriched in deuterium).

[0167] All compounds described herein, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., in the form of hydrates and solvates).

[0168] In one aspect, the present invention is directed to an intermediate compound, or a pharmaceutically acceptable salt thereof, which can be used in the synthesis of the compounds of the present invention. For example, said intermediate compound is in some embodiments one of the intermediate compounds, or a pharmaceutically acceptable salt thereof, of any one of examples 1 to 18 disclosed herein. In some embodiments the compound of the present invention is selected from any of the intermediate compounds, or a pharmaceutically acceptable salt thereof, disclosed in any one of examples 1 to 18 herein.

[0169] The compounds of the present invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist as stereoisomers, enantiomers and diastereomers. Accordingly, the scope of the instant invention is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form and stereoisomeric mixtures of any chemical structures disclosed herein, unless the stereochemistry is specifically identified. If the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated.

[0170] The term “stereoisomer” or “stereoisomerically pure” compound as used herein refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of the other enantiomer and diastereomers of the compound. A typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.

[0171] In some embodiments, the compound as defined herein is stereoisomerically pure.

[0172] Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents, for example as outlined in the example section.

[0173] Pharmaceutical composition

[0174] The present invention also relates to a pharmaceutical composition comprising, for example as an active ingredient, a pharmaceutically effective amount of a compound as disclosed herein. In some embodiments, said pharmaceutical composition comprises a therapeutically effective amount of a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

[0175] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of Formula (I):

[0176] Formula (I) wherein X1is N or C(R6);

[0177] R6is H or F

[0178] X2is N or C(H);

[0179] R1is C1-6 alkyl optionally substituted with one or more, identical or different, R13, or a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6-membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic;

[0180] R13is C1-3 alkoxy;

[0181] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen;

[0182] R2is of Formula (II):

[0183] Formula (II)

[0184] X3is O or N(R4);

[0185] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl; R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl; R7is individually F or CH3, and n is 0, 1 or 2; or n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s);

[0186] R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0187] In one aspect, the present invention relates to a pharmaceutical composition comprising a compound of selected from: pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0188] While a compound as disclosed herein for use in therapy may be administered in the form of the raw chemical compound, it is often preferred to introduce the active ingredient, optionally in the form of a pharmaceutically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and / or other customary pharmaceutical auxiliaries.

[0189] In some embodiments, the invention provides pharmaceutical compositions comprising a compound as disclosed herein or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, and, optionally, other therapeutic and / or prophylactic ingredients, known and used in the art. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Examples of excipients and their use may be found in Remington’s Pharmaceutical Sciences 20th Edition (Lippincott Williams & Wilkins, 2000).

[0190] A therapeutic amount or therapeutically effective amount or dose refers to that amount of active ingredient, i.e. the compounds or compositions as disclosed herein, which treats, alleviates, abates, or reduces the severity of symptoms of a disease in a subject, such as ameliorates one or more symptoms of the condition or the condition itself. A therapeutic amount of a compound as described herein may improve patient survival, increase survival time or rate, diminish symptoms, make an injury, disease, or condition (e.g, a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve a patient’s physical or mental well-being.

[0191] Therapeutic efficacy and toxicity, e.g. ED50, may be determined by standard pharmacological procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and may be expressed by ratio between plasma levels resulting in therapeutic effects and plasma ratios resulting in toxic effects. Pharmaceutical compositions exhibiting large therapeutic indexes are preferred. In some embodiments, the therapeutically effective dose of a compound as disclosed herein is in the range of about 0.01 mg / kg to about 100 mg / kg bodyweight / day.

[0192] The dose administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and regimen, and the result desired, and the exact dosage should of course be determined by the practitioner.

[0193] To administer refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

[0194] Biological activity

[0195] As demonstrated in Example 19 compounds of the present invention are capable of modulating TREM2. Thus, in some embodiments, the compound of the present invention is a TREM2 modulator, such as a TREM2 agonist. The assay described in Example 19 may be used to assess and characterize a compound’s ability to act as an agonist of TREM2. In some embodiments the compounds of the present invention are useful for the activation of TREM2. In some embodiments the compounds of the present invention activates TREM2. In some embodiments the compounds of the present invention enhances TREM2 activity. In some embodiments, a compound of the present invention induces phosphorylation of a kinase that interacts with the TREM2 / DAP12 signalling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b. In some embodiments the compounds of the present invention enhances or activates TREM2 signalling through DAP12. In some embodiments the compounds of the present invention enhances or activates TREM2-induced phosphorylation levels of the Syk kinase. In some embodiments, a compound of the present invention induces or enhances phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more as compared to a control value. The potency of compounds of the present invention are in some embodiments expressed as ECso corresponding to the concentration of compound able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response. In some embodiments the compounds of the present invention has an ECso value of less than 1000 nM, such as an ECso value between 100 nM and 1000 nM, such as an ECso value between 10 nM and 100 nM, such as an an EC50 value between 1 nM and 10 nM, such as an ECso value <1 nM. The ECso value may be determined as described in Example 19.

[0196] In some embodiments the compounds of the present invention are capable of increasing the expression of one or more TREM2 regulated genes. In some embodiments the compounds of the present invention increases the expression of one or more TREM2 regulated genes. In some embodiments, the compounds of the present invention are capable or increasing one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119. In some embodiments the compounds of the present invention increases expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119.

[0197] In some embodiments, a compound of the present invention increases expression levels, such as brain expression levels, if the level expression of the gene in a sample treated with the compound is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100% or more as compared to a control value; such as is increased by at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 3.5-fold, 4-fold, 5-fold, or more as compared to a control value (e.g. untreated control / vehicle).

[0198] In some embodiments, the compound of the present invention is suitable for use as a pharmaceutical agent. Hence, in some embodiments, the compound has suitable pharmacological activity, such as target efficacy, affinity and / or selectivity. In some embodiments, the compound has suitable Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties. For example, in some embodiments, the compound has acceptable levels of off-target effects, including low hERG channel (human Ether-a-go-go-Related Gene) inhibition, low off-target toxicity, genotoxicity, carcinogenicity, and / or hepatotoxicity. In some embodiments, the compound demonstrates suitable pharmacokinetics, such as bioavailability, half-life, and / or clearance. In some embodiments, the compound demonstrates suitable pharmacodynamics, such as efficacy and / or potency. In some embodiments, the compound demonstrates chemical stability and / or metabolic stability. Said parameters may be assessed by conventional in vitro tests, animal studies and / or clinical trials known by the skilled person. In some embodiments, the compound demonstrates suitable characteristics for oral formulation using pharmaceutically acceptable excipients. For example, the compound demonstrates suitable solubility in relevant media.

[0199] Medical use

[0200] Being modulators of TREM2, the compounds of the present invention are of use in the treatment of diseases and disorders of a living body, including human. As used herein, the term “treatment” includes treatment, prevention, and / or alleviation or amelioration of one or more diseases and disorders or one or more symptoms of a disease or disorder. In one aspect, the compound as described herein is for use as a medicament.

[0201] In one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a loss of function of TREM2. In one aspect, the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a condition associated with a mutation in TREM2.

[0202] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a neurodegenerative disease.

[0203] In some embodiments, a compound as described herein is used in treating a neurodegenerative disease that is characterized by a loss of function of TREM2. In some embodiments, a compound as described herein is used in treating a neurodegenerative disease that is characterized by a mutation in TREM2.

[0204] In one aspect, the present invention relates to a method for enhancing or increasing

[0205] TREM2 activity in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0206] In one aspect, the present invention relates to method for one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM1 19; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0207] In some embodiments, the neurodegenerative disease is a tauopathy. Tautopathies depicts some neurodegenerative disorders characterized by tau deposits in the brain, with symptoms of dementia and parkinsonism. In some embodiments, the neurodegenerative disease is a tauopathy selected from the group consisting of Primary age related tauopathy (PART), globular glial tauopathy, Chronic traumatic encephalopathy (CTE), Progressive supranuclear palsy, Corticobasal degeneration, diffuse neurofibrillary tangles with calcification (DNTC), Frontotemporal dementia (FTD), and FTD with parkinsonism-17 (FTD with parkinsonism linked to chromosome 17; FTDP-17).

[0208] In some embodiments, the neurodegenerative disease is a neurodegenerative disorders associated with TDP-43 (TDP-43 proteinopathies or TDP-43-opathies). Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases.

[0209] In some embodiments, the neurodegenerative disease is a TDP-43 proteinopathy selected from the group consisting of amyotrophic lateral sclerosis (ALS), sporadic amyotrophic lateral sclerosis (sALS), familial amyotrophic lateral sclerosis (fALS), frontotemporal lobar degeneration / disease (FTLD), Primary lateral sclerosis (PLS), progressive muscular atrophy (PMA), FTLD-tau, FTLD-FUS (bvFTLD), FTLD-TDP-43 or FTLD-ll (types a, b and c), Facial onset sensory and motor neuronopathy (FOSMN), Limbic-predominant age-related TDP-43 encephalopathy (LATE), cerebral age-related TDP-43 with sclerosis (CARTS), Guam Parkinson-dementia complex (G-PDC) and ALS (G-ALS), Kii ALS / PDC, amyotrophic lateral sclerosis / parkinsonism-dementia complex of Guam (ALS-PDC), Multisystem proteinopathy (MSP; also referred to as inclusion body myopathy, IBM, associated with early-onset Paget disease of the bone and FTLD dementia), Perry disease, and disorders with concomitant TDP-43 pathology, including Alzheimer’s disease (AD) and Chronic traumatic encephalopathy (CTE).

[0210] In some embodiments, the neurodegenerative disease is Multisystem proteinopathy (MSP). MSP is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and / or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders (IBMPFD, IBMPFD / ALS).

[0211] In some embodiments, the neurodegenerative disease is a synucleinopathy. Synucleinopathies (also called a-Synucleinopathies) are neurodegenerative diseases characterised by the abnormal accumulation of aggregates of alpha-synuclein protein in neurons, nerve fibres or glial cells.

[0212] In some embodiments, the neurodegenerative disease is a synucleinopathy selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), neuroaxonal dystrophies, Alzheimer's Disease with Amygdalar Restricted Lewy Bodies (AD / ALB).

[0213] In some embodiments, the neurodegenerative disease is cognitive deficit and / or memory loss. In some embodiments, the neurodegenerative disease is dementia. In some embodiments, the neurodegenerative disease is dementia selected from the group consisting of Alzheimer’s disease, Parkinson’s disease dementia, Huntingtons disease dementia, vascular dementia, HIV dementia, frontotemporal dementia, dementia with lewy bodies, prion disease dementia, argyrophilic grain dementia, dementia pugilistica, Guadeloupean parkinsonism with dementia, neurofibrillary tangle- predominant dementia, tangle only dementia, Down’s syndrome, semantic dementia, familial British dementia, familial Danish dementia, and other dementias caused by another medical condition such as brain tumors, subdural hematoma, endocrine disorders, nutritional deficiencies, infections, immune disorders, liver or kidney failure, metabolic disorders such as Kufs disease, some leukodystrophies, some neurological disorders such as epilepsy, and multiple sclerosis.

[0214] Disorders of peripheral nerves (peripheral neuropathy) are the most common neurological complications of systemic amyloidosis. In some embodiments, the neurodegenerative disease is peripheral amyloidosis (peripheral neuropathy in systemic amyloidosis).

[0215] In some embodiments, the neurodegenerative disease is a demyelinating disorder. In some embodiments, the neurodegenerative disease is a demyelinating disorder of the central nervous system, CNS. In some embodiments, the demyelinating disorder is a myelinoclastic or demyelinating disorder, such as selected from the group consisting of multiple sclerosis, neuromyelitis optica (Devic’s disease) and idiopathic inflammatorydemyelinating diseases. In some embodiments, the demyelinating disorder is a leukodystrophic or dysmyelinating disorder, such as selected from the group consisting of CNS neuropathies such as vitamin B12 deficiency, central pontine myelinolysis, myelopathies such as tabes dorsalis (syphilitic myelopathy), leukoencephalopathies and leukodystrophies.

[0216] In some embodiments, the neurodegenerative disease is a demyelinating disorder of the peripheral nervous system, PNS. In some embodiments, the demyelinating disorder is selected from the group consisting of Guillain-Barre syndrome and its chronic counterpart, chronic inflammatory demyelinating polyneuropathy; Anti-MAG peripheral neuropathy; Charcot-Marie-Tooth disease and its counterpart Hereditary neuropathy with liability to pressure palsy; Copper deficiency-associated conditions (peripheral neuropathy, myelopathy, and rarely optic neuropathy); and Progressive inflammatory neuropathy.

[0217] In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD). In some embodiments, the neurodegenerative disease is Alzheimer’s disease (AD) with the R47H mutation. In some embodiments, the neurodegenerative disease is early Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD). In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the neurodegenerative disease is Parkinson’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease (NHD). In some embodiments, the neurodegenerative disease is FTLD-like syndrome. In some embodiments, the neurodegenerative disease is Huntington disease. In some embodiments, the neurodegenerative disease is Amyotrophic lateral sclerosis (ALS). In some embodiments, the neurodegenerative disease is multiple sclerosis (MS). In some embodiments, the neurodegenerative disease is Guillain-Barre syndrome. In some embodiments, the neurodegenerative disease is chronic inflammatory demyelinating polyneuropathies. In some embodiments, the neurodegenerative disease is progressive subcortical gliosis. In some embodiments, the neurodegenerative disease is Charcot-Marie-Tooth disease. In some embodiments, the neurodegenerative disease is prion disease, such as prion protein cerebral amyloid angiopathy. In some embodiments, the neurodegenerative disease is stroke. In some embodiments, the neurodegenerative disease is cerebral amyloid angiopathy (CAA). In some embodiments the neurodegenerative disease is fragile X-associated tremor ataxia syndrome (FXTAS). In some embodiments the neurodegenerative disease is herpes simplex virus (HSV) encephalitis. In some embodiments the neurodegenerative disease is HIV-associated neurocognitive disorders (HAND). In some embodiments the neurodegenerative disease is progressive supranuclear palsy (PSP). In some embodiments the neurodegenerative disease is corticobasal degeneration. In some embodiments the neurodegenerative disease is Hallevorden-Spatz disease. In some embodiments the neurodegenerative disease is pallido-ponto-nigral degeneration. In some embodiments the neurodegenerative disease is postencephalitic parkinsonism. In some embodiments the neurodegenerative disease is subacute sclerosing panencephalitis (SSPE). In some embodiments the neurodegenerative disease is retinal degeneration (e.g., macular degeneration).

[0218] In some embodiments the neurodegenerative disease is a Leukoencephalopathy. Leukoencephalopathy (leukodystrophy-like diseases) is a term that describes all of the brain white matter diseases, whether their molecular cause is known or unknown. In some embodiments the neurodegenerative disease is a Leukoencephalopathy selected from the group consisting of Progressive multifocal leukoencephalopathy, Toxic leukoencephalopathy, Leukoencephalopathy with vanishing white matter, Leukoencephalopathy with neuroaxonal spheroids, Reversible posterior leukoencephalopathy syndrome, Megalencephalic leukoencephalopathy with subcortical cysts, and Hypertensive leukoencephalopathy. In some embodiments, the neurodegenerative disease is ALSP (Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia).

[0219] In some embodiments the neurodegenerative disease is selected from the group consisting of cerebral autosomal dominant arteriopathy with subcortical infarcts or leukoencephalopathy; cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; and retinal vasculopathy with cerebral leukoencephalopathy (or cerebroretinal vasculopathy).

[0220] In some embodiments the neurodegenerative disease is a leukodystrophy. In some embodiments the neurodegenerative disease is vanishing white matter disease (VWM). Leukodystrophies are a group of rare, genetic disorders that affect the white matter of the brain. In some embodiments the neurodegenerative disease is a leukodystrophy selected from the group consisting of metachromatic leukodystrophy (MLD, also known as globoid cell leukodystrophy), Krabbe disease, Canavan disease, X-linked adrenoleukodystrophy, Alexander disease, hypomyelinating leukodystrophy type 7 (4H syndrome), Pelizaeus-Merzbacher disease, cerebrotendineous xanthomatosis and leukoendephalopathy with vanishing white matter. In some embodiments the neurodegenerative disease is adult-onset autosomal dominant leukodystrophy (ADLD). In some embodiments the neurodegenerative disease is X-linked adrenoleukodystrophy (X-ALD). In some embodiments the neurodegenerative disease is Nasu-Hakola disease also known as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL).

[0221] In some embodiments, the neurodegenerative disease is a transmissible spongiform encephalopathy (TSE), including Creutzfeldt-Jakob disease, Gerstmann-Straussler- Scheinker disease (GSS), kuru, and fatal familial insomnia.

[0222] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising administering a compound, or a pharmaceutically acceptable salt thereof, as described herein to a subject in need thereof.

[0223] In one aspect, the present invention relates to a method for treatment of a neurodegenerative disease comprising one or more steps of administering a therapeutically effective amoubt of a compound, or a pharmaceutically acceptable salt thereof, as defined herein to a subject in need thereof.

[0224] In some embodiments, the subject is a mammal, such as a human.

[0225] In one aspect, the present invention relates to use of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the manufacture of a medicament for treatment of a neurodegenerative disease.

[0226] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder associated with dysfunction of Colony stimulating factor 1 receptor (CSF1R, also known as macrophage colony-stimulating factor receptor / M- CSFR, or cluster of differentiation 115 / CD115). In some embodiments the disease or disorder associated with dysfunction of CSF1R is a neurodegenerative disease associated with dysfunction of CSF1 R.

[0227] In some embodiments the disease or disorder is caused by a heterozygous CSF1 R mutation, a homozygous CSF1 R mutation, a splice mutation in the csflr gene, a missense mutation in the csflr gene, a mutation in the catalytic kinase domain of CSF1R, a mutation in an immunoglobulin domain of CSF1 R, a mutation in the ectodomain of CSF1R, a loss-of-function mutation in CSF1R. In some embodiments the disease or disorder result from a change (e.g. increase, decrease or cessation) in the activity of CSF1R and / or a decrease or cessation in the activity of CSF1R.

[0228] In some embodiments the neurodegenerative disease associated with dysfunction of CSF1R is a Leukoencephalopathy.

[0229] In some embodiments the neurodegenerative disease associated with dysfunction of CSF1R is selected from the group consisting of: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), CSF1 R-related leukoencephalopathy, hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS), pigmentary orthochromatic leukodystrophy (POLD), pediatric-onset leukoencephalopathy, congenital absence of microglia, brain abnormalities neurodegeneration and dysosteosclerosis (BANDDOS), and Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

[0230] In some embodiments the neurodegenerative disease is a condition associated with dysfunction of ATP- binding cassette transporter 1 (ABCD1).

[0231] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a lysosomal storage disorder (LSD). Most lysosomal storage disorders cause progressive neurodegeneration leading to early death.

[0232] In some embodiments the LSD is a lipidoses, such as a lipidoses selected from the group consisting of cholesteryl ester storage disease, fucosidosis, Schindler disease and Wolman disease.

[0233] In some embodiments the LSD is a sphingolipidoses, such as a sphingolipidoses selected from the group consisting of Fabry disease, Gaucher disease, Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (MLD), Niemann-Pick disease (Types A, B and C), Sandhoff disease, Farmer disease, multiple sulfatase deficiency and Tay-Sachs disease.

[0234] In some embodiments the LSD is a mucopolysaccharidoses, such as a mucopolysaccharidoses selected from the group consinting of Hunter syndrome, Hurler syndomre, Hurler-Scheie syndrome, Scheie syndrome, Sanfilippo syndrome (A, B, C, D), Morquio syndrome, Maroteaux-Lamy syndrome, Sly syndrome and Natowicz syndrome.

[0235] In some embodiments the LSD is selected from the group consisting of Batten disease, cyctinosis, Danon disease and Pompe disease.

[0236] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of a disease or disorder of the bones and / or joints. In some embodiments said disease or disorder is selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia and dysosteoplasia. In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of autism spectrum disorders, autism and Aspergers syndrome.

[0237] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of traumatic brain injuries (TBI) and spinal cord injuries. Traumatic brain injuries (TBI), may also be known as intracranial injuries. Traumatic brain injuries occur when an external force traumatically injures the brain. Spinal cord injuries (SCI) include any injury to the spinal cord that is caused by trauma instead of disease. In some embodiments the TBI is chronic traumatic encephalopathy (CTE).

[0238] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of muscular dystrophy such as myotonic dystrophy (DM) including Type 1 DM (DM1) and Type 2 DM (DM2).

[0239] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of inflammation. In some embodiments said inflammation is selected from the group consisting of inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, and certain bowel conditions including Inflammatory bowel disease (IBD).

[0240] A reduction in the functional levels of TREM2 results in dysregulation of lipid metabolism. In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of dysregulated lipid metabolism. In certain embodiments, the dysregulated lipid metabolism comprises increased intracellular and / or extracellular accumulation of one or more lipids. In some embodiments said dysregulated lipid metabolism is atherosclerosis.

[0241] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of metabolic syndrome and conditions associated with metabolic syndrome, such as obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, and alcoholic and non-alcoholic steatohepatitis,

[0242] In one aspect, the present invention relates to the compound, or a pharmaceutically acceptable salt thereof, as defined herein for use in the treatment of Amyloidosis, including AL amyloidosis (immunoglobulin light chain amyloidosis), AA amyloidosis (secondary amyloidosis), familial amyloidosis, familial systemic amyloidosis, Wild-type amyloidosis (senile systemic amyloidosis) and Localized amyloidosis.

[0243] In some embodiments, the neurodegenerative disease is Alzheimer’s disease. In some embodiments, the neurodegenerative disease is Nasu-Hakola disease. In some embodiments, the neurodegenerative disease is frontotemporal dementia. In some embodiments, the method comprises administering to the subject a compound as described herein, or a pharmaceutical composition comprising a compound as described herein.

[0244] The compounds of the present invention may be used to treat an animal patient belonging to any classification. Examples of such animals include mammals such as humans, rodents, dogs, cats, zoo animals and farm animals. In some embodiments, the subject referred to herein is a mammal, such as a human.

[0245] The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, unless otherwise specified. Accordingly, the scope of the methods and uses herein is to be understood to encompass methods and uses employing all such forms.

[0246] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” In some embodiments, a provided combination, or composition thereof, is administered in combination with another therapeutic agent. In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents. In some embodiments, the method includes coadministering one or more additional therapeutic agent. Examples of therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for Parkinson’s disease, rheumatoid arthritis, Alzheimer’s disease, Nasu- Hakola disease, frontotemporal dementia, multiple sclerosis, prion disease, or stroke. In some embodiments, the therapeutic agents the combinations of the present invention may also be combined with include, without limitation: treatments for a disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD). As used herein, the term “combination,” “combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with the present invention. For example, a combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[0247] In one aspect, the present invention relates to a method of treating a condition associated with a loss of function of TREM2 comprising administering to a subject a therapeutically effective amount of a compound selected from:

[0248] embodiments, the condition is a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke. In some embodiments, the neurodegenerative disease is Alzheimer’s Disease. Methods of manufacturing

[0249] Compounds of the present invention may be prepared according to any conventional methods of chemical synthesis known by the skilled person, e.g. those described in the working examples. The starting materials for the processes described in the present application are either commercially available or may readily be prepared by conventional methods known by the skilled artisan from commercially available chemicals. Reaction conditions such as reaction temperature, solvent and reagents for the Schemes in this section may be found in the experimental section herein. The end products of the reactions described herein may be isolated by conventional technique such as extraction, crystallisation, distillation, chromatography etc.

[0250] The compounds provided in herein can be synthesized in accordance with the methods outlined in this and subsequent sections. However, it is important to note that these synthetic procedures are only examples, and individuals with knowledge in the field can also employ alternative methods to synthesize the disclosed compounds. The provided general synthetic procedures and specific examples are merely illustrative and should not restrict the scope of this disclosure in any way.

[0251] In general, the compounds represented by Formula (I) can be synthesized using the schemes described below. The variables used in these schemes correspond to the variables defined for Formula (I), unless stated otherwise. All starting materials can be obtained commercially, or they may already be known in the field and can be synthesized using established procedures. It is also possible to synthesize starting materials using the procedures described in this document. The examples provided herein can guide the selection of suitable reaction conditions, such as solvent, reaction temperature, and reagents, for the discussed schemes. In the following schemes, Y represents either a hydrogen or a methyl group and the other groups are as defined herein. The synthetic scheme and representative examples provided do not encompass all possible methods for synthesizing the compounds described and claimed in this application. Skilled individuals in the field will be aware of additional methods. Furthermore, it is possible to perform the various synthetic steps described above in a different sequence or order to obtain the desired compounds. Purification methods for the compounds described in this document are well-known in the field. Scheme 1 :

[0252] Scheme 2:

[0253] R3B(OH)2R1NH2

[0254] Metal catalyzed coupling and hydrol Amide coupling ysis

[0255] Step 1 Step 2

[0256] Scheme 3:

[0257] In one aspect, the present invention relates to a method for synthesizing a compound of Formula (I) comprising one or more of the steps described above. In one aspect, the present invention relates to a method for manufacturing a compound of Formula (I) as defined herein, said method comprising the steps of reacting a compound of Formula (SI):

[0258] Formula (SI) wherein Y is H or methyl, and X1and X2are as defined herein, with a) a compound of Formula (Sil):

[0259] Formula (Sil) wherein Y is H or methyl, and X3, R5, R7and n are as defined in classes and subclasses herein, both singly and in combination, to introduce the moiety of Formula (II) in position R2of Formula (I); b) R3B(OH)2via metal catalyzed coupling and hydrolysis to introduce the R3moiety of Formula (I); and c) R1NH2 via amide coupling to introduce the -N(H)-R1moiety of Formula (I).

[0260] Steps a), b) and c) may be performed in any order, e.g. in the order of a)-b)-c), b)-c)-a) or a)-c)-b).

[0261] Items

[0262] 1 . A compound of Formula (I),

[0263] Formula (I) wherein

[0264] X1is N or C(R6);

[0265] R6is H or F;

[0266] X2is N or C(H);

[0267] R1is C1-6 alkyl optionally substituted with one or more, identical or different, R13, or a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6- membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6- membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic;

[0268] R13is C1-3 alkoxy;

[0269] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen;

[0270] R2is of Formula (II):

[0271] Formula (II) X3is O or N(R4);

[0272] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0273] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;

[0274] R7is individually H, F or CH3, and n is 0, 1 or 2; or n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s);

[0275] R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof. A compound of Formula (I),

[0276] Formula (I) wherein

[0277] X1is N or C(R6);

[0278] R6is H or F

[0279] X2is N or C(H); and at least one X1and X2is N;

[0280] R1is a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6- membered heteroaryl, and 5-membered heteroaryl;

[0281] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0; and halogen;

[0282] R2is of Formula (V): Formula (V)

[0283] X3is O or N(R4);

[0284] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0285] R5is pyrazolyl optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;

[0286] R7is individually H, F or CH3, and n is 0, 1 or 2;

[0287] R3is phenyl substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0288] 3. The compound according to any one of the preceding items, wherein X1is N, or a pharmaceutically acceptable salt thereof.

[0289] 4. The compound according to any one of the preceding items, wherein X1is C(R6), and R6is H or F, or a pharmaceutically acceptable salt thereof.

[0290] 5. The compound according to any one of the preceding items, wherein R6is H, or a pharmaceutically acceptable salt thereof.

[0291] 6. The compound according to any one of the preceding items, wherein X1is C(H), or a pharmaceutically acceptable salt thereof.

[0292] 7. The compound according to any one of the preceding items, wherein X2is N, or a pharmaceutically acceptable salt thereof.

[0293] 8. The compound according to any one of the preceding items, wherein X2is C(H), or a pharmaceutically acceptable salt thereof.

[0294] 9. The compound according to any one of the preceding items, wherein at least one X1and X2is N, or a pharmaceutically acceptable salt thereof.

[0295] 10. The compound according to any one of the preceding items, wherein X1is N and X2is N; X1is N and X2is C(H); or X1is C(H) and X2is N, or a pharmaceutically acceptable salt thereof.

[0296] 11 . The compound according to any one of the preceding items, wherein X1is N and X2is N, or a pharmaceutically acceptable salt thereof.

[0297] 12. The compound according to any one of the preceding items, wherein X1is N and X2is C(H), or a pharmaceutically acceptable salt thereof.

[0298] 13. The compound according to any one of the preceding items, wherein X1is C(H) and X2is N, or a pharmaceutically acceptable salt thereof.

[0299] 14. The compound according to any one of the preceding items, wherein R1is a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6- membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6- membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic, or a pharmaceutically acceptable salt thereof.

[0300] 15. The compound according to any one of the preceding items, wherein R1a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6-membered heteroaryl, and 5-membered heteroaryl; and

[0301] R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen, or a pharmaceutically acceptable salt thereof.

[0302] 16. The compound according to any one of the preceding items, wherein R1is phenyl, or a pharmaceutically acceptable salt thereof.

[0303] 17. The compound according to any one of the preceding items, wherein R1is phenyl substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof.

[0304] 18. The compound according to any one of the preceding items, wherein R1is phenyl substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0305] 19. The compound according to any one of the preceding items, wherein R1is phenyl substituted with -CH3, or a pharmaceutically acceptable salt thereof.

[0306] 20. The compound according to any one of the preceding items, wherein R1is fj , or a pharmaceutically acceptable salt thereof.

[0307] 21 . The compound according to any one of the preceding items, wherein R1is phenyl substituted with CN, or a pharmaceutically acceptable salt thereof.

[0308] 22. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is phenyl substituted with CN and -CH3, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is phenyl substituted with CN and cyclopropyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is phenyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is phenyl substituted with -OCH3, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl substituted with -CH3, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with -OC1-3 alkyl, or a pharmaceutically acceptable salt thereof. compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl substituted with -OCH3, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl optionally substituted with halogen, or a pharmaceutically acceptable salt thereof. compound according to any one of the preceding items, wherein R1is a 6- membered heteroaryl substituted with Cl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein the 6- membered heteroaryl is pyridinyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is pyridinyl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is pyridinyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof. 44. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0309] 45. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with -CH3, or a pharmaceutically acceptable salt thereof.

[0310] 46. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0311] 47. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with -OCH3, or a pharmaceutically acceptable salt thereof.

[0312] 48. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with halogen, or a pharmaceutically acceptable salt thereof.

[0313] 49. The compound according to any one of the preceding items, wherein R1is pyridinyl substituted with Cl, or a pharmaceutically acceptable salt thereof.

[0314] 50. The compound according to any one of the preceding items, wherein the pyridinyl is 2-pyridinyl, or a pharmaceutically acceptable salt thereof.

[0315] 51. The compound according to any one of the preceding items, wherein the pyridinyl is 3-pyridinyl, or a pharmaceutically acceptable salt thereof.

[0316] 52. The compound according to any one of the preceding items, wherein the pyridinyl is 4-pyridinyl, or a pharmaceutically acceptable salt thereof.

[0317] 53. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof.

[0318] 54. The compound according to any one of the preceding items, wherein R1is a 5- membered heteroaryl optionally substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof.

[0319] 55. The compound according to any one of the preceding items, wherein R1is a 5- membered heteroaryl optionally substituted with 1 to 3 substituents individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen, or a pharmaceutically acceptable salt thereof.

[0320] 56. The compound according to any one of the preceding items, wherein R1is a 5- membered heteroaryl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof. 57. The compound according to any one of the preceding items, wherein R1is a 5- membered heteroaryl substituted with -CH3, or a pharmaceutically acceptable salt thereof.

[0321] 58. The compound according to any one of the preceding items, wherein the 5- membered heteroaryl is pyrazolyl, or a pharmaceutically acceptable salt thereof.

[0322] 59. The compound according to any one of the preceding items, wherein R1is pyrazolyl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0323] 60. The compound according to any one of the preceding items, wherein R1is pyrazolyl substituted with -CH3, or a pharmaceutically acceptable salt thereof.

[0324] 61 . The compound according to any one of the preceding items, wherein R1is

[0325] / , or a pharmaceutically acceptable salt thereof.

[0326] 62. The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof.

[0327] 63. The compound according to any one of the preceding items, wherein R1is or a pharmaceutically acceptable salt thereof.

[0328] 64. The compound according to any one of the preceding items, wherein the 5- membered heteroaryl is oxazolyl, or a pharmaceutically acceptable salt thereof.

[0329] 65. The compound according to any one of the preceding items, wherein R1is oxazolyl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0330] 66. The compound according to any one of the preceding items, wherein R1is oxazolyl, or a pharmaceutically acceptable salt thereof.

[0331] 67. The compound according to any one of the preceding items, wherein R1is

[0332] , or a pharmaceutically acceptable salt thereof. 68. The compound according to any one of the preceding items, wherein the 5- membered heteroaryl is isoxazolyl, or a pharmaceutically acceptable salt thereof.

[0333] 69. The compound according to any one of the preceding items, wherein R1is isoxazolyl optionally substituted with C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0334] 70. The compound according to any one of the preceding items, wherein R1is isoxazolyl, or a pharmaceutically acceptable salt thereof.

[0335] 71 . The compound according to any one of the preceding items, wherein R1is , or a pharmaceutically acceptable salt thereof.

[0336] 72. The compound according to any one of the preceding items, wherein R13is OCH3, or a pharmaceutically acceptable salt thereof.

[0337] 73. The compound according to any one of the preceding items, wherein R1is - (CH2)2OCH3, or a pharmaceutically acceptable salt thereof.

[0338] 74. The compound according to any one of the preceding items, wherein R1is - (CH2)3OCH3, or a pharmaceutically acceptable salt thereof.

[0339] 75. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0340] 76. The compound according to any one of the preceding items, wherein R14is CH3, or a pharmaceutically acceptable salt thereof.

[0341] 77. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl optionally substituted with =0, or a pharmaceutically acceptable salt thereof.

[0342] 78. The compound according to any one of the preceding items, wherein R14is - C(O)CH3, or a pharmaceutically acceptable salt thereof.

[0343] 79. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl optionally substituted with =0 and / or -N(CH3)2, or a pharmaceutically acceptable salt thereof.

[0344] 80. The compound according to any one of the preceding items, wherein R14is C1-3 alkyl optionally substituted with 1 to 3 halogens, or a pharmaceutically acceptable salt thereof.

[0345] 81 . The compound according to any one of the preceding items, wherein R14is C3-5 cycloalkyl, or a pharmaceutically acceptable salt thereof. 82. The compound according to any one of the preceding items, wherein R14is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0346] 83. The compound according to any one of the preceding items, wherein R14is C1-3 alkoxy, or a pharmaceutically acceptable salt thereof.

[0347] 84. The compound according to any one of the preceding items, wherein R14is - OCH3, or a pharmaceutically acceptable salt thereof.

[0348] 85. The compound according to any one of the preceding items, wherein R14is CN, or a pharmaceutically acceptable salt thereof.

[0349] 86. The compound according to any one of the preceding items, wherein R14is =0, or a pharmaceutically acceptable salt thereof.

[0350] 87. The compound according to any one of the preceding items, wherein R14is halogen, or a pharmaceutically acceptable salt thereof.

[0351] 88. The compound according to any one of the preceding items, wherein R14is Cl, or a pharmaceutically acceptable salt thereof.

[0352] 89. The compound according to any one of the preceding items, wherein R2is of Formula (Ila):

[0353] Formula (Ila) or a pharmaceutically acceptable salt thereof.

[0354] 90. The compound according to any one of the preceding items, wherein R2is of Formula (lib):

[0355] Formula (lib) or a pharmaceutically acceptable salt thereof.

[0356] 91 . The compound according to any one of the preceding items, wherein X3is O, or a pharmaceutically acceptable salt thereof.

[0357] 92. The compound according to any one of the preceding items, wherein R2is of Formula (III):

[0358] Formula (III) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein X3is N(R4), or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R2is of Formula (IV):

[0359] Formula (IV) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein n is 0, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein n is 1 , or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R2is of Formula (V):

[0360] Formula (V) wherein

[0361] X3is O or N(R4);

[0362] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl; and

[0363] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R2is of Formula (Va):

[0364] Formula (Va) or a pharmaceutically acceptable salt thereof. The compound according to any one of the preceding items, wherein R2is of Formula (Vb):

[0365] Formula (Vb) or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R2is of Formula (VI):

[0366] Formula (VI) wherein

[0367] X3is O or N(R4);

[0368] R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;

[0369] R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl; and

[0370] R7is selected from the group consisting of H, F or CH3, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R2is of Formula (Via):

[0371] Formula (Via) or a pharmaceutically acceptable salt thereof.

[0372] 102. The compound according to any one of the preceding items, wherein R2is of Formula (Vlb):

[0373] Formula (Vlb) or a pharmaceutically acceptable salt thereof.

[0374] 103. The compound according to any one of the preceding items, wherein R2is of Formula (Vic):

[0375] Formula (Vic) or a pharmaceutically acceptable salt thereof.

[0376] 104. The compound according to any one of the preceding items, wherein R2is of Formula (Vid):

[0377] Formula (Vid) or a pharmaceutically acceptable salt thereof.

[0378] 105. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is H, and R5is 1- methyl-1 H-pyrazol-4-yl)piperazin-1 -yl, or a pharmaceutically acceptable salt thereof.

[0379] 106. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is H, and R5is 1 - cyclopropyl-1 H-pyrazol-4-yl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0380] 107. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is CH3, and R5is 1 -methyl-1 H-pyrazol-4-yl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0381] 108. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is O, R7is CH3, and R5is 1-cyclopropyl-1 H-pyrazol-4-yl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0382] 109. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is N(CH2CH3), R7is H, and R5is 1 -methyl-1 H-pyrazol-4-yl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0383] 110. The compound according to any one of the preceding items, wherein R2is of Formula (VI), (Via), (Vlb), (Vic) or (Vid), and X3is N(CH2CH3), R7is H, and R5is 1-cyclopropyl-1 H-pyrazol-4-yl)piperazin-1-yl, or a pharmaceutically acceptable salt thereof.

[0384] 111. The compound according to any one of the preceding items, wherein X3is O, or a pharmaceutically acceptable salt thereof.

[0385] 112. The compound according to any one of the preceding items, wherein X3is N(R4) and R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl, or a pharmaceutically acceptable salt thereof.

[0386] 113. The compound according to any one of the preceding items, wherein X3is N(R4) and R4is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0387] 114. The compound according to any one of the preceding items, wherein R4is ethyl, or a pharmaceutically acceptable salt thereof.

[0388] 115. The compound according to any one of the preceding items, wherein R7is individually H, F or CH3, and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R7is individually F or CH3, and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein n is 0, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein n is

[0389] 1 , or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein n is

[0390] 2, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R7is H, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R7is CH3, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s), or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R5is pyrazolyl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R5is of Formula (XI):

[0391] Formula (XI) wherein

[0392] R8is C1-3 alkyl, C3-6 cycloalkyl or H, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, wherein R5is of Formula (XII): Formula (XII) wherein

[0393] R8is C1-3 alkyl, C3-6 cycloalkyl or H, or a pharmaceutically acceptable salt thereof.

[0394] 126. The compound according to any one of the preceding items, wherein R8is C1-6 alkyl, or a pharmaceutically acceptable salt thereof.

[0395] 127. The compound according to any one of the preceding items, wherein R8is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.

[0396] 128. The compound according to any one of the preceding items, wherein R8is -CH3, or a pharmaceutically acceptable salt thereof.

[0397] 129. The compound according to any one of the preceding items, wherein R8is C3-6 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0398] 130. The compound according to any one of the preceding items, wherein R8is cyclopropyl, or a pharmaceutically acceptable salt thereof.

[0399] 131. The compound according to any one of the preceding items, wherein R5is or a pharmaceutically acceptable salt thereof.

[0400] 132. The compound according to any one of the preceding items, wherein R5is , or a pharmaceutically acceptable salt thereof.

[0401] 133. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof.

[0402] 134. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof. 135. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof.

[0403] 136. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof.

[0404] 137. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof.

[0405] 138. The compound according to any one of the preceding items, wherein R2 pharmaceutically acceptable salt thereof.

[0406] 139. The compound according to any one of the preceding items, wherein R3is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

[0407] 140. The compound according to any one of the preceding items, wherein R3is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN.

[0408] 141 . The compound according to any one of the preceding items, wherein R3is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN.

[0409] 142. The compound according to any one of the preceding items, wherein R3is phenyl substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, with the proviso that the phenyl is substituted with a halogen or CN in the para position, or a pharmaceutically acceptable salt thereof.

[0410] 143. The compound according to any one of the preceding items, wherein R3is of Formula (XIII):

[0411] Formula (XIII) wherein

[0412] R9is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[0413] R10is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN;

[0414] R11is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN; and

[0415] R12is H, halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, or CN, or a pharmaceutically acceptable salt thereof.

[0416] 144. The compound according to any one of the preceding items, wherein R9is H, or a pharmaceutically acceptable salt thereof.

[0417] 145. The compound according to any one of the preceding items, wherein R9is halogen, such as F or Cl, or a pharmaceutically acceptable salt thereof.

[0418] 146. The compound according to any one of the preceding items, wherein R9is C1-3 alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

[0419] 147. The compound according to any one of the preceding items, wherein R9is CN, or a pharmaceutically acceptable salt thereof.

[0420] 148. The compound according to any one of the preceding items, wherein R10is H, or a pharmaceutically acceptable salt thereof.

[0421] 149. The compound according to any one of the preceding items, wherein R10is halogen, such as F, or a pharmaceutically acceptable salt thereof.

[0422] 150. The compound according to any one of the preceding items, wherein R11is halogen, such as F or Cl, or a pharmaceutically acceptable salt thereof.

[0423] 151. The compound according to any one of the preceding items, wherein R11is C1-3 alkyl, such as -CH3, or a pharmaceutically acceptable salt thereof.

[0424] 152. The compound according to any one of the preceding items, wherein R11is C1-3 haloalkyl, such as -CF3, or a pharmaceutically acceptable salt thereof.

[0425] 153. The compound according to any one of the preceding items, wherein R11is C1-3 haloalkyl, such as -CHF2, or a pharmaceutically acceptable salt thereof. 154. The compound according to any one of the preceding items, wherein R11is CN, or a pharmaceutically acceptable salt thereof.

[0426] 155. The compound according to any one of the preceding items, wherein R11is C1-3 alkoxy , or a pharmaceutically acceptable salt thereof.

[0427] 156. The compound according to any one of the preceding items, wherein R11is -OCH3, or a pharmaceutically acceptable salt thereof.

[0428] 157. The compound according to any one of the preceding items, wherein R12is H, or a pharmaceutically acceptable salt thereof.

[0429] 158. The compound according to any one of the preceding items, wherein R12is halogen, such as F, or a pharmaceutically acceptable salt thereof.

[0430] 159. The compound according to any one of the preceding items, wherein R10is H and R12is H, or a pharmaceutically acceptable salt thereof.

[0431] 160. The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of:

[0432] 161 . The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein R3is selected from the group consisting of: 162. The compound according to any one of the preceding items, wherein R3is: acceptable salt thereof.

[0433] 163. The compound according to any one of the preceding items, wherein R3 pharmaceutically acceptable salt thereof.

[0434] 164. The compound according to any one of the preceding items, wherein R3 pharmaceutically acceptable salt thereof.

[0435] 165. The compound according to any one of the preceding items, wherein R3 pharmaceutically acceptable salt thereof.

[0436] 166. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of: 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpyrimidine-4-carboxamide;

[0437] 2-(4-chloro-2-fluorophenyl)-N-(2-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0438] 2-(4-chloro-2-fluorophenyl)-N-(3-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide; 2-(4-chloro-2-fluorophenyl)-N-(4-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0439] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(o- tolyl)pyrimidine-4-carboxamide;

[0440] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-2-yl)pyrimidine-4-carboxamide;

[0441] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-3-yl)pyrimidine-4-carboxamide;

[0442] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-4-yl)pyrimidine-4-carboxamide;

[0443] 2-(4-chloro-2-fluorophenyl)-N-(isoxazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0444] 2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-4-yl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide;

[0445] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (oxazol-2-yl)pyrimidine-4-carboxamide;

[0446] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(1- methyl-1 H-pyrazol-5-yl)pyrimidine-4-carboxamide;

[0447] 2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-3-yl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide;

[0448] 2-(4-chloro-2-fluorophenyl)-N-(4-cyanophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;

[0449] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(3- methylpyridin-4-yl)pyrimidine-4-carboxamide;

[0450] 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylisonicotinamide;

[0451] 6-(4-chloro-2-fluorophenyl)-4-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpicolinamide; and 2-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4-yl)piperazin-1- yl)-N-phenylpyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof. . The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist. . The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound enhances or activates TREM2 signaling through DAP12; and / or wherein the compound induces phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b; and / or wherein the compound enhances TREM2-induced phosphorylation levels of the Syk kinase. . The compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, wherein the compound increases the expression of one or more TREM2 regulated genes, such as wherein the compound increases the expression of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119.. A pharmaceutical composition comprising a compound according to any one of the preceding items, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.. The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use as a medicament. . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use in the treatment of a condition associated with a loss of function of TREM2, such as for use in the treatment of a condition associated with a mutation of TREM2. . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use in the treatment of a neurodegenerative disease.. The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, wherein for use in in the treatment of a neurodegenerative disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD). . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use in the treatment of a neurodegenerative disease selected from the group consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease and stroke. . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusionbody myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis. . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use according to any one of items 171 to 176, wherein said compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg bodyweight / day. . The compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for use according to any one of items 171 to 177, wherein said compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery. . A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method comprising administering a therapeutically effective amount of a compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, to a subject in need thereof.. Use of a compound according to any one of items 1 to 169, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to item 170, for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease. . A method of enhancing or increasing TREM2 activity, such as a method of one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, according to any one of items 1 to 169. . A compound selected from:

[0452] pharmaceutically acceptable salt thereof.

[0453] 183. A pharmaceutical composition comprising a compound of item 182, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0454] 184. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0455] 185. A pharmaceutical composition comprising a compound of item 184, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0456] 186. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0457] 187. A pharmaceutical composition comprising a compound of item 186, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0458] 188. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0459] 189. A pharmaceutical composition comprising a compound of item 188, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0460] 190. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0461] 191. A pharmaceutical composition comprising a compound of item 190, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0462] 192. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0463] 193. A pharmaceutical composition comprising a compound of item 192, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0464] 194. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. 195. A pharmaceutical composition comprising a compound of item 194, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0465] 196. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0466] 197. A pharmaceutical composition comprising a compound of item 196, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0467] 198. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0468] 199. A pharmaceutical composition comprising a compound of item 198, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0469] 200. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. 201. A pharmaceutical composition comprising a compound of item 200, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0470] 202. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0471] 203. A pharmaceutical composition comprising a compound of item 202, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0472] 204. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0473] 205. A pharmaceutical composition comprising a compound of item 204, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0474] 206. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. 207. A pharmaceutical composition comprising a compound of item 206, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0475] 208. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0476] 209. A pharmaceutical composition comprising a compound of item 208, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0477] 210. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof.

[0478] 211. A pharmaceutical composition comprising a compound of item 210, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0479] 212. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. 213. A pharmaceutical composition comprising a compound of item 212, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0480] 214. The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. . A pharmaceutical composition comprising a compound of item 214, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents. . The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. . A pharmaceutical composition comprising a compound of item 216, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents. . The compound of item 182, wherein the compound is: or a pharmaceutically acceptable salt thereof. . A pharmaceutical composition comprising a compound of item 218, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents. Examples

[0481] Abbreviations LCMS Conditions:

[0482] Condition A

[0483] LCMS Column- Waters XSelect CSH C18 (2.1 x 50 mm; 2.5 urn), Gradient from 95%

[0484] [10 mM aqueous Ammonium bicarbonate, pH 9.5] and 5% [Acetonitrile] to 2% [10 mM aqueous Ammonium bicarbonate, pH 9.5] and 98% [Acetonitrile] in 2 min. This mobile phase composition was held up to 2.70 min. Followed by changing to the initial gradient 95% [10 mM aqueous Ammonium bicarbonate, pH 9.5] and 5% [Acetonitrile], which was held up to 3.20 min. Flow: 0.60 ml / min.

[0485] Condition B

[0486] LCMS Column- Waters XBridge BEH C18 XP (2.1 x 50 mm; 2.5 pm), Gradient from 80% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 900 / 60 / 40)] and 20% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 100 / 540 / 360)] to 0% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 900 / 60 / 40)] and 100% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 100 / 540 / 360)] in 2 min. This mobile phase composition was held up to 4.00 min. Followed by changing to the initial gradient 80% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 900 / 60 / 40)] and 20% [10 mM Ammonium acetate (Water / Methanol / Acetonitrile 100 / 540 / 360)], which was held up to 5.00 min. Flow: 0.60 ml / min.

[0487] General procedure A (Amide coupling):

[0488] To a solution of 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxylic acid (1.00 Eq) in DMF (1.0 mL) were added HATLI (1.50 Eq), DIPEA (2.50 Eq) and corresponding amine (2.00-4.00 Eq). After addition, the reaction mixture was stirred at room temperature for 2-48 hours. The crude was purified by method A, B or C to afford the desired corresponding product.

[0489] Purification Methods

[0490] Method A: Reverse phase preparative HPLC: Buchi Pure Chromatography Systems, ReproSil-Pur Basic-C18 (133 x 25 mm, 10pm), 40-95% acetonitrile in aqueous 10mM ammonium bicarbonate, flow: 30 ml / min.

[0491] Method B: Reverse phase preparative HPLC: Agilent 1260 / 1290 Infinity II series with UV-detector and MSD with electron spray ionization, Gemini NX C18 (150 * 30 mm, 5um), 15-95% acetonitrile in aqueous 10mM ammonium bicarbonate pH 9.5; flow: 40 ml / min.

[0492] Method C: Reverse phase preparative HPLC: Agilent 1260 / 1290 Infinity II series with UV-detector and MSD with electron spray ionization, Gemini NX C18 (150 * 30 mm, 5um), 15-95% methanol in aqueous 0.1% TFA; flow: 40 ml / min. General procedure B (Substitution followed by amide coupling):

[0493] To a solution of 1-ethyl-2-(1-methyl-1 H-pyrazol-4-yl)piperazine hydrochloride (1.00 Eq) in DMF (3.0 mL) was added 2,6-dichloropyrimidine-4-carboxylic acid (1.3 Eq) followed by triethylamine (3.00 Eq). After addition, the reaction mixture was stirred at 100 °C for 2 hours. HATLI (2.00 Eq) was added and the reaction was stirred for 15 min at room temperature. Corresponding amine (2.20 Eq) was added followed by DIPEA (3.00 Eq). After addition, the reaction mixture was stirred at room temperature overnight. The crude mixture was filtered and purified by reverse phase preparative HPLC (Buchi Pure Chromatography Systems, ReproSil-Pur Basic-C18 (133 x 25 mm, 10pm), 20-95% acetonitrile in aqueous 10mM ammonium bicarbonate) to afford the corresponding product.

[0494] General procedure C (Suzuki Coupling):

[0495] A solution of chloride substituted heteroaromatic starting material (1.00 Eq) in 1,4- dioxane (0.6-1.5 mL) and water (0.3-0.8 mL) was purged using a nitrogen stream for 5- 10 min. Corresponding boronic acid (1.20-1.40 Eq), K2CO3 (3.00 Eq) and Tetrakis(triphenylphosphine)palladium (0) (0.05-0.1 Eq) were added under nitrogen atmosphere. After addition, the reaction mixture was stirred at 60-80°C for 18-48 hours. The volatiles were removed in vacuo. To the residue was added water (15 mL) and EtOAc (15 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. The crude was purified by reverse phase preparative HPLC (Buchi Pure Chromatography Systems, ReproSil-Pur Basic- Ci 8 (133 x 25 mm, 10pm), 30-95% acetonitrile in aqueous 20mM ammonium bicarbonate) to afford the corresponding product.

[0496] Example 1 2-(4-Chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-N- phenylpyrimidine-4-carboxamide

[0497] Step-1

[0498] Preparation of methyl 2-chloro-6-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxylate:

[0499] To a stirred solution of 2,6-dichloropyrimidine-4-carboxylic acid (1.35 g, 1.40 Eq, 7.00 mmol) and 2-(1-methyl-1 H-pyrazol-4-yl) morpholine (836 mg, 1.00 Eq, 5.00 mmol) in DMF (18.5 mL) was added triethylamine (1.52 g, 2.08 mL, 3.00 Eq, 15.0 mmol). After addition, the reaction mixture was stirred at 100 °C for 4 hours. The volatiles were removed in vacuo. To the residue was added EtOAc (25 mL) and water (25 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 25 mL). The aqueous phase was acidified to pH 1-2 and extracted with EtOAc (4 x 25 mL). All the combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to afford crude 2-chloro-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)pyrimidine-4-carboxylic acid as orange solid (LCMS Condition A: Rt = 0.74 min. m / z 324.0 [M+H]+). To a solution of the obtained crude mixture in DMF (19.0 mL) was added potassium carbonate (1.26 g, 1.83 Eq, 9.13 mmol), followed by iodomethane (1.73 g, 761 pL, 2.44 Eq, 12.2 mmol). After addition, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and water (50 mL) and DCM (50 mL) were added. The phases were separated, and the aqueous phase was extracted with DCM (2 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered, and reduced in vacuo to afford the crude product. The crude mass was purified by normal phase column chromatography (0-100% ethyl acetate in heptane) to afford methyl 2-chloro-6-(2-(1-methyl-1 H-pyrazol- 4-yl)morpholino)pyrimidine-4-carboxylate (1.00 g, 59% yield) as light yellow solid. 1 H NMR (400 MHz, DMSO) 5 7.74 (s, 1 H), 7.53 - 7.41 (m, 2H), 4.81 - 4.17 (m, 3H), 4.03 - 3.93 (m, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.63 (td, J = 11.6, 2.8 Hz, 1H), 3.14 (s, 2H).

[0500] LCMS Condition A: Rt = 1.21 min, m / z 338.0 [M+H]+.

[0501] Step-2

[0502] Preparation of 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxylic acid:

[0503] A solution of methyl 2-chloro-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)pyrimidine-4- carboxylate (734 mg, 1.00 Eq, 2.17 mmol) in 1,4-Dioxane (7.0 mL) and Water (3.5 mL) was degassed using a nitrogen stream for 15 minutes. 4-chloro-2-fluorophenyl-boronic acid (455 mg, 1.20 Eq, 2.61 mmol) and Tetrakis(triphenylphosphine)palladium(0) (251 mg, 0.10 Eq, 217 pmol) were added. The mixture was stirred at 70°C for 4 hours. All volatiles were removed in vacuo and aqueous hydrochloric acid (0.5 M, 50 mL) and EtOAc were added. The phases were separated, and the aqueous phase was extracted with EtOAc (5 x 50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to afford the crude product. The crude was purified by reverse phase column chromatography (0-50% acetonitrile in water) to afford 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxylic acid (480 mg, 53% yield) as white solid.

[0504] 1 H NMR (400 MHz, MeOD) 5 8.09 (t, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.43 (s, 1H), 7.41 - 7.35 (m, 2H), 4.77 - 4.32 (m, 3H), 4.11 (ddd, J = 11.8, 3.6, 1.8 Hz, 1 H), 3.89 (s, 3H), 3.79 (td, J = 11.6, 2.8 Hz, 1 H), 3.43 - 3.32 (m, 2H).

[0505] LCMS Condition A: Rt = 1.02 min, m / z 418.1 [M+H]+.

[0506] Step-3

[0507] Preparation of 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)-N-phenylpyrimidine-4-carboxamide:

[0508] To a solution of 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxylic acid (15 mg, 1.00 Eq, 36 pmol) in DMF (1.0 mL) was added HATU (20 mg, 1.50 Eq, 54 pmol). The reaction mixture was stirred for 15 min at room temperature and DIPEA (12 mg, 16 pL, 2.50 Eq, 90 pmol) and aniline (6.7 mg, 6.6 pL, 2.00 Eq, 72 pmol) were added. After addition, the reaction mixture was stirred at room temperature for 2 hours. The crude was purified by reverse phase preparative HPLC (Buchi Pure Chromatography Systems, ReproSil-Pur Basic-C18 (133 x 25 mm, 10pm), 40-95% acetonitrile in aqueous 10mM ammonium bicarbonate) to afford 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpyrimidine-4-carboxamide (4.0 mg, 23% yield).

[0509] 1 H NMR (400 MHz, MeOD) 5 8.25 (t, J = 8.3 Hz, 1 H), 7.79 - 7.71 (m, 2H), 7.67 (s, 1 H), 7.54 (s, 1 H), 7.46 - 7.28 (m, 5H), 7.25 - 7.14 (m, 1H), 4.73 - 4.35 (m, 3H), 4.08 (ddd, J = 11.7, 3.7, 1.8 Hz, 1 H), 3.90 (s, 3H), 3.77 (td, J = 11.6, 2.8 Hz, 1H), 3.29 - 3.16 (m, 2H).

[0510] LCMS Condition B: Rt = 2.38 min, m / z 493.2 [M+H]+.

[0511] Examples 2 to 15

[0512] Following general procedure A, using example amines in box below resulted in corresponding examples 2 to 15.

[0513] Amines used to synthesize Examples 2 to 15:

[0514] HNMR, LCMS, purification method and yield percentage information of examples 2 to 15 are provided in the table below:

[0515]

[0516]

[0517]

[0518] Example 16

[0519] 2-(4-Chloro-2-fluorophenyl)-6-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-N- phenylisonicotinamide

[0520] Step 1

[0521] Preparation of methyl 2-chloro-6-(2-(1-methyl-1H-pyrazol-4- yl)morpholino)isonicotinate: To a solution of 2-(1-methyl-1 H-pyrazol-4-yl)morpholine (120 mg, 1.00 Eq, 718 pmol) and methyl 2,6-dichloroisonicotinate (201 mg, 1.36 Eq, 976 pmol) in DMF (3.78 mL) was added DIPEA (278 mg, 375 pL, 3.00 Eq, 2.15 mmol). After addition, the reaction mixture was stirred at 100°C overnight. The volatiles were removed in vacuo. DCM (15 mL) and water (15 mL) were added. The phases were separated, and the aqueous phase was extracted with DCM (2 x 15 mL). The combined organic phases were dried over sodium sulfate, filtered and reduced in vacuo. The crude was purified by normal phase column chromatography (0-100% ethyl acetate in heptane) to afford methyl 2- chloro-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)isonicotinate (162 mg, 67.0 %) as beige solid.

[0522] 1 H NMR (400 MHz, CDCI3) 5 7.52 (d, J = 0.8 Hz, 1 H), 7.41 (s, 1 H), 7.13 (d, J = 1.0 Hz, 1 H), 7.07 (d, J = 1.0 Hz, 1 H), 4.55 (dd, J = 10.3, 2.8 Hz, 1 H), 4.29 - 4.20 (m, 1 H), 4.13 - 4.01 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.82 - 3.71 (m, 1 H), 3.19 - 3.08 (m, 1 H), 3.08 - 2.98 (m, 1 H).

[0523] LCMS Condition A: Rt = 1 .63 min, m / z 337.1 [M+H]+.

[0524] Step 2

[0525] Preparation of methyl 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)isonicotinate:

[0526] A solution of methyl 2-chloro-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)isonicotinate (162 mg, 1.00 Eq, 481 pmol) in 1 ,4-Dioxane (3.21 mL) and water (1.60 mL) was degassed using nitrogen stream for 15 minutes. Potassium carbonate (199 mg, 84.5 pL, 3.00 Eq, 1.44 mmol) was added, followed by 4-chloro-2-fluorophenyl-boronic acid (101 mg, 1.20 Eq, 577 pmol) and Tetrakis(triphenylphosphine)palladium(0) (55.6 mg, 0.10 Eq, 48.1 pmol). After addition, the reaction mixture was stirred at 70 °C overnight. The volatiles were removed in vacuo. DCM (30 mL) and water (15 mL) were added. The phases were separated, and the aqueous phase was extracted with DCM (1 x 30 mL). The combined organic phases were dried over sodium sulfate, filtered and reduced in vacuo. The crude was purified by normal phase column chromatography (0- 5% methanol in dichloromethane) to afford methyl 2-(4-chloro-2-fluorophenyl)-6-(2-(1- methyl-1 H-pyrazol-4-yl)morpholino)isonicotinate (129 mg, 0.20 mmol, 42 % yield). LCMS Condition A: Rt = 2.01 min, m / z 431.1 [M+H]+.

[0527] Step 3

[0528] Preparation of 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)isonicotinic acid:

[0529] To a solution of methyl 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)isonicotinate (129 mg, 1 Eq, 299 pmol) in THF (2.0 mL) and MeOH (0.22 mL) was added an aqueous solution of lithium hydroxide (10.8 mg, 449 pL, 1.0 molar, 1.50 Eq, 449 pmol). After addition, the reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. Hydrochloric acid (aqueous, 1 M, 20 mL) and EtOAc (20 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to afford 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)isonicotinic acid (108 mg, 87 % yield) as light yellow solid.

[0530] LCMS Condition A: Rt = 1.13 min, m / z 417.1 [M+H]+.

[0531] Step 4

[0532] Preparation of 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)-N-phenylisonicotinamide:

[0533] To a solution of 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)isonicotinic acid (22 mg, 1.00 Eq, 53 pmol) in DMF (1.0 mL) was added HATU (30 mg, 1.50 Eq, 79 pmol). The reaction mixture was stirred for 15 minutes at room temperature and DIPEA (17 mg, 23 pL, 2.50 Eq, 130 pmol) and aniline (9.87 mg, 9.6 pL, 2.00 Eq, 110 pmol) were added. After addition, the reaction mixture was stirred at room temperature for 2 hours. The crude was purified by reverse phase preparative HPLC (Agilent 1260 / 1290 Infinity II series with UV-detector and MSD with electron spray ionization, Gemini NX C18 (150 * 30 mm, 5um), 15-95% acetonitrile in aqueous 10mM ammonium bicarbonate pH 9.5; flow: 40 ml / min) to afford 2-(4-chloro-2- fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-phenylisonicotinamide (15 mg, 58 % yield).

[0534] 1 H NMR (400 MHz, CDCI3) 6 7.97 (t, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (s, 1 H), 7.42 (d, J = 2.1 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.24 - 7.10 (m, 4H), 4.61 (dd, J = 10.3, 2.7 Hz, 1 H), 4.37 (d, J = 12.8 Hz, 1 H), 4.19 (d, J = 12.8 Hz, 1 H), 4.10 (ddd, J = 11.5, 3.5, 1.7 Hz, 1 H), 3.89 (s, 3H), 3.87 - 3.77 (m, 1H), 3.18 (ddd, J = 12.7, 11.3, 3.5 Hz, 1H), 3.10 (dd, J = 12.9, 10.3 Hz, 1 H).

[0535] LCMS Condition B: Rt = 2.17 min, m / z 492.2 [M+H]+.

[0536] Example 17

[0537] 6-(4-Chloro-2-fluorophenyl)-4-(2-(1-methyl-1H-pyrazol-4-yl)morpholino)-N- phenylpicolinamide

[0538] Step 1

[0539] Preparation of 4-chloro-6-(4-chloro-2-fluorophenyl)picolinic acid:

[0540] A solution of methyl 4,6-dichloropicolinate (388 mg, 1.00 Eq, 1.88 mmol) in 1,4- Dioxane (3.80 mL) and Water (1.90 mL) was degassed under nitrogen stream for 15 minutes. Potassium carbonate (781 mg, 331 pL, 3.00 Eq, 5.65 mmol) was added followed by 4-chloro-2-fluorophenyl-boronic acid (394 mg, 1.20 Eq, 2.26 mmol) and Tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.10 Eq, 188 pmol). After addition, the reaction mixture was stirred at 70 °C overnight. The volatiles were removed in vacuo. The aqueous phase was acidified to pH 1 with aqueous hydrochloric acid (1 M). The aqueous phase was extracted with EtOAc (5x). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo. The crude was dissolved in THF (8.0 mL) and MeOH (0.89 mL) and lithium hydroxide (96.5 mg, 4.03 mL, 1.0 molar, 1.50 Eq, 4.03 mmol) was added. After addition, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. Hydrochloric acid (aqueous, 1 M HCI, 50 mL) and EtOAc (50 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered and reduced in vacuo to afford crude 4-chloro-6-(4-chloro-2- fluorophenyl)picolinic acid (702 mg, 1.3 mmol, 49 % yield) as a beige solid. LCMS Condition A: Rt = 1.13 min, m / z 285.9 [M+H]+.

[0541] Step 2

[0542] Preparation of 2-(4-chloro-2-fluorophenyl)-6-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)isonicotinic acid:

[0543] To a solution of crude 4-chloro-6-(4-chloro-2-fluorophenyl)picolinic acid (183 mg, 1 Eq, 640 pmol) in DMF (2.0 mL) was added HATLI (268 mg, 1.10 Eq, 704 pmol). After addition, the reaction mixture was stirred for 15 min at room temperature. DIPEA (207 mg, 279 pL, 2.50 Eq, 1.60 mmol) was added followed by aniline (119 mg, 117 pL, 2.00 Eq, 1.28 mmol). After addition, the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo. To the crude was added DCM (25 mL) and water (25 mL). The phases were separated and the aqueous phase was extracted with DCM (2 x 25 mL). The combined organic phases were dried over sodium sulfate, filtered, and reduced in vacuo. The crude was purified by normal phase column chromatography (0-20% ethyl acetate in heptane) to afford 4-chloro-6-(4-chloro-2- fluorophenyl)-N-phenylpicolinamide (80 mg, 35 % yield).

[0544] LCMS Condition A: Rt = 2.34 min, m / z 361.0 [M+H]+.

[0545] Step 3

[0546] Preparation of 6-(4-chloro-2-fluorophenyl)-4-(2-(1 -methyl-1 H-pyrazol-4- yl)morpholino)-N-phenylpicolinamide: To a solution of 4-chloro-6-(4-chloro-2-fluorophenyl)-N-phenylpicolinamide (78 mg, 1.00 Eq, 220 pmol) and 2-(1-methyl-1 H-pyrazol-4-yl) morpholine (110 mg, 3.00 Eq, 650 pmol) in DMSO (2.0 mL) was added DIPEA (33 mg, 1.20 Eq, 260 pmol). The reaction vial was heated in a microwave (Biotage Initiator) for 18 hours at 130°C. The crude was purified by reverse phase preparative HPLC (Waters Preparative system, X-Select CSH Prep C18 OBD (100 x 30 mm; 5 pm), 15-95% acetonitrile in aqueous 10mM ammonium bicarbonate pH 9.5; flow: 38 ml / min) to afford 6-(4-chloro-2-fluorophenyl)-4- (2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-phenylpicolinamide (30 mg, 28% yield) as white solid.

[0547] 1 H NMR (400 MHz, DMSO) 5 10.38 (s, 1H), 8.21 (t, J = 8.5 Hz, 1 H), 7.88 - 7.80 (m, 2H), 7.76 (s, 1 H), 7.65 - 7.55 (m, 2H), 7.49 (d, J = 0.8 Hz, 1 H), 7.47 - 7.43 (m, 2H), 7.41 - 7.35 (m, 2H), 7.18 - 7.09 (m, 1 H), 4.59 (dd, J = 10.5, 2.7 Hz, 1 H), 4.12 - 4.01 (m, 2H), 3.91 (d, J = 12.5 Hz, 1H), 3.82 (s, 3H), 3.74 (td, J = 11.6, 2.8 Hz, 1 H), 3.07 (td, J = 12.1 , 3.6 Hz, 1 H), 2.99 (dd, J = 12.6, 10.5 Hz, 1 H).

[0548] LCMS Condition B: Rt = 2.33 min, m / z 492.2 [M+H]+.

[0549] Example 18 2-(4-Chloro-2-fluorophenyl)-6-(4-ethyl-3-(1 -methyl-1 H-pyrazol-4-yl)piperazin-1-yl)~

[0550] N-phenylpyrimidine-4-carboxamide

[0551] Step 1

[0552] Preparation of 2-chloro-6-(4-ethyl-3-(1 -methyl-1 H-pyrazol-4-yl)piperazin-1 -yl)-N- phenylpyrimidine-4-carboxamide:

[0553] Following general procedure B, using aniline (71.9 mg, 70.5 pL, 2.20 Eq, 772 pmol) resulted in crude 2-chloro-6-(4-ethyl-3-(1 -methyl-1 H-pyrazol-4-yl)piperazin-1-yl)-N- phenylpyrimidine-4-carboxamide (70 mg, 23% yield).

[0554] LCMS Condition A: Rt = 3.17 min, m / z 426.2 [M+H]+.

[0555] Step 2 Preparation of 2-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1 -methyl-1 H-pyrazol-4- yl)piperazin-1-yl)-N-phenylpyrimidine-4-carboxamide:

[0556] Following general procedure C, using 2-chloro-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4- yl)piperazin-1-yl)-N-phenylpyrimidine-4-carboxamide (36 mg, 1.00 Eq, 85 pmol) and (4- chloro-2-fluorophenyl)boronic acid (18 mg, 1.20 Eq, 0.10 mmol) resulted in 2-(4-chloro- 2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4-yl)piperazin-1-yl)-N- phenylpyrimidine-4-carboxamide (24 mg, 55% yield) as off-white solid.

[0557] 1 H NMR (400 MHz, MeOD) 5 8.25 - 8.09 (m, 1 H), 7.79 - 7.66 (m, 2H), 7.64 - 7.57 (m, 1 H), 7.52 - 7.46 (m, 1 H), 7.43 - 7.11 (m, 6H), 3.89 (d, J = 1.8 Hz, 3H), 3.58 - 3.20 (m, 8H), 3.18 - 3.00 (m, 1H), 2.78 - 2.61 (m, 1 H), 2.46 - 2.24 (m, 1H), 2.24 - 2.07 (m, 1 H). LCMS Condition B: Rt = 2.40 min, m / z 520.2 [M+H]+.

[0558] Example 19- Biological evaluation

[0559] Human TREM2, in vitro Measurement of Triggering Receptor Expressed on Myeloid Cells 2 activity using cellular phosphorylation of Spleen Tyrosine Kinase (“Syk”) Assay

[0560] Cell line:

[0561] HEK-293 cells were co-transfected with separate plasmids encoding TREM2 and DAP12 to generate a stable cell line. After antibiotic selection, functional clone pool analysis and two successive limiting dilutions, the final clone “HEK293 / DAP12+TREM2” underwent a qPCR analysis and a pharmacological validation.

[0562] Assay

[0563] TREM2 signaling through DAP12 was monitored in the HEK293 / DAP12+TREM2 stable cell line by measuring the phosphorylation levels of the Syk kinase using the commercially available AlphaLISA SureFire Ultra p-SYK (Tyr525 / 526) Assay Kit (PerkinElmer #ALSU-PSYK), based on the Perkin Elmer AlphaScreen / AlphaLISA technology.

[0564] Compounds are transferred to the test plate and tested in full dose response, 8 concentrations in quadruplicate data points. Compound serial dilutions were performed at Cybi-Felix instrument in 100% DMSO and the dose response curves were assembled in automated fashion in 384MPT at Hamilton STARIet instrument. All the stock solutions were prepared at 20 mM in 100% DMSO. For compounds testing, the starting concentration was 100 pM, dilution steps 1:6. A different concentration’s range was adapted for compound’s activity based on the preliminary results. Finally, a 384MPT reformatted for all compounds at 8 concentrations, quadruplicates, was used as “mother to child” process with a CyBi®-Well dispenser in which 1 pL of each compound was moved into a destination plate pre-filled with 65.6 pL of EMEM cell culture medium (BIOWHITTAKER_cat.BE12-125F), thus obtaining 3x concentrated compounds working solution. In columns 1-2 and 23-24 the control wells were added. In particular, dose response curves of a reference control agonist were included in column 1 and 24 as reference control agonist (Reference control agonists used include Human TREM2 polyclonal Antibody AF1828: R&D Systems; Human TREM2 monoclonal Antibody MAB1828: R&D Systems). The dose response curves were tested starting at 30 pM, dilution step 1:6. Both “source” compound plate and “destination” compound plate were barcoded and a relationship between the two plates was thus generated.

[0565] HEK293 / DAP12+TREM2 cells were cultured in EMEM medium supplemented with IX Penicillin / Streptomycin (BIOWHITTAKER_cat.DE17-602E), ULTRAGLUTAMINE I 200mM, 10% Fetal Bovine Serum plus antibiotics referred to as “HEK293 Culture Medium”. The day before the experiment, cells were detached by gentle wash with DPBS, followed by 5 min incubation at 37°C with Trypsin solution. Cells were then diluted in HEK293 Culture Medium without antibiotics, counted and seeded into 384- well poly-D-Lysine coated microplates black / clear bottom (GREINER 781946) at a density of 10,000 cells / well in 25 pL / well by the use of a MATRIX WellMate dispenser. Plates were placed into a humidified cell culture incubator at 37°C with 5% CO2 until the experimental day. 20-24 hours after seeding mature medium was removed and replaced with 10 pL / well of EMEM cell medium supplemented with 0.1% Pluronic F-68 non-ionic surfactant (Thermofisher, 24040032), referred to as “Assay Buffer”, using the CyBi®-Well instrument. Then 5 pL / well of Assay Buffer containing 3X concentrated test compounds or the reference control agonist (in 0.5 % final DMSO concentration) were added to the cells with the CyBi®-Well instrument. Cell plates were incubated for 30 min into a humidified cell culture incubator at 37°C with 5% CO2., then the medium was removed by manually discard. 20 pL / well of lysis buffer were dispensed using the CyBi®-Well instrument and plates were incubated for 10 min at room temperature on a plate shaker (350rpm). Then, 10 pL / well of lysate were transferred to the Alpha plates. The CyBi®-Well instrument was used to dispense 5 pL / well of AlphaLISA Acceptor Bead Solution in IX Immunoassay buffer (Perkin Elmer AL000F). Then the plates were sealed with Heat sealing foil, shaked for 2 minutes (350 rpm) and incubated for 1 hour at room temperature. Following the incubation with the AlphaLISA Acceptor Bead Solution, the CyBi®-Well instrument was used to dispense 5 pL / well of AlphaLISA Donor Bead Solution in IX Immunoassay buffer. The plates were sealed with Heat sealing foil, shaked for 2 minutes (350 rpm) and then incubated for 1 hour at room temperature. At the end of the incubation an AlphaLISA signal was acquired from the donor and acceptor beads using the Pherastar FSX instrument, a high throughput multi-modal microplate reader calibrated to the plate type with the AlphaLISA mirror and filter-set in 384-well mode, 680-615 nanometer excitation wavelength. The total integration time was 0,60 seconds with a 0,30 second excitation time and a gain of 3600.

[0566] Data analysis was performed with Genedata Screener® software and reported compounds activity as % effect in relation to the normalization standards. The AlphaScreen Signal was normalized versus Neutral Controls (Assay buffer plus 0.5% DMSO final cone.) and Stimulator Controls (EC oof the reference control agonist in Assay buffer plus 0.5% DMSO final cone.) in order to obtain the Activity[%] for each well. The normalization places the compound activity values on an equivalent scale and makes them comparable across plates or different compound batches. Therefore, the compound activity values were scaled (based on the two references) to a common range (two-point normalization). The following equation was used by the software to normalize the signal values to the desired signal range:

[0567] N(x) = CR + [((x - < cr >) / (< sr > - < cr >)) ■ (SR - CR)] where: x is the signal value of a well; < cr > is the median of the signal values for the Central Reference wells of a plate (median of Neutral Controls); < sr > is the median of the signal values for the Scale Reference wells of a plate (median of Stimulator Controls); CR is the desired median normalized value for the Central Reference (0) and SR is the desired median normalized value for the Scale Reference (100).

[0568] The final equation to calculate the Activity% can be simplified as follow:

[0569] % Activity = 100 ■ (x - <NeutralControls>) I (<StimulatorControls> - <NeutralControls>) where full activation corresponds to % Activity = 100. The fitting of the dose-response curve of each test compound is performed in the Analyzer module of the Screener software on the normalized values and applying the “smart fit” strategy. This strategy allowed an automatic selection between the “Constant Fit” and the “Hill Fit” model calculating which fit model best matched the experimental data. The Constant Fit was applied when no change of activity was detected across the measured concentrations, and the corresponding compounds were further classified as “inactive”. The Hill Fit was applied when the observed activity significantly changed with the compound concentration. In case of Hill Fit, Hill equation was used to determine the concentration at which activity reaches 50% of maximum level, i.e., AC50.

[0570] Y = So + ((Sinf -So) / (1 + (10L°9AC5° 1 10x)n)) where X is Log10 of compound concentration.

[0571] The equation has four parameters:

[0572] • Zero Activity (SO) - Activity level at zero concentration of test compound;

[0573] • Infinite Activity (Sinf) - Activity level at infinite concentration of test compound;

[0574] • ACso - Concentration at which activity reaches 50% of maximum level. This term corresponds to EC50 in this assay;

[0575] . Hill coefficient (n) - Measure of the slope at AC50.

[0576] The potency of the test compounds was expressed as EC50 corresponding to the test compound concentration able to activate the phospho-Syk AlphaScreen signal to 50% of the maximal response.

[0577] The EC50 values measured in this assay for the exemplified compounds is set out in the table below: wherein “A “denotes an ECso value <10 nM, “B” denotes an ECso value between 10 nM and 100 nM, “C” denotes an ECso value between 100 and 1000 nM, “D” denotes an ECso value greater than 1000 nM. Regarding Emax values, “+” denotes < 75% , “++” denotes 75-110% and “+++” denotes >110% maximal response relative to the maximal response of the reference agonist (8-(4-chloro-2-fluorophenyl)-2,3-dimethyl-6- [(2S)-2-(1-methyl-1 H-pyrazol-4-yl)morpholin-4-yl]-3H,4H-[1 ,3]diazino[5,4-d]pyrimidin-4- one).

[0578] References

[0579] Colonna, M. et al. (2016) Nat Rev Neurosci 17, 201-207

[0580] Deczkowska, A. et al. (2020) Perspective, 181 , 6, 1207-1217

[0581] Hammond, T. R. (2019) Immunity, 50, 4 5955-974

[0582] Suarez-Calvet, M. et al. (2016) EMBO Mol Med, 8, 466-476

[0583] Yamazaki, K. et al. (2015) Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 13(3), 324-326 Paloneva BM, J. et al. (2001) Neurology, 56 (11) 1552-1558;

[0584] Ulrich J. D. et al. (2017) Neuron., 19;94(2):237-248)

[0585] Atagi, Y. et al. (2015) J Biol Chem., 290(43), 26043-50

[0586] Kleinberger, G. et al (2014) Sci Transl Med., 2, 6 (243):243

Claims

Claims1 . A compound of Formula (I),Formula (I) whereinX1is N or C(R6);R6is H or FX2is N or C(H);R1is C1-6 alkyl optionally substituted with one or more, identical or different, R13, or a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6- membered heteroaryl, 5-membered heteroaryl, C4-6 cycloalkyl, and 5- to 6- membered saturated or partly unsaturated heterocyclic ring having one heteroatom selected from N and O, wherein said 5- to 6-membered heterocyclic ring is monocyclic or bicyclic;R13is C1-3 alkoxy;R14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0 and halogen;R2is of Formula (II):Formula (II)X3is O or N(R4);R4is selected from the group consisting of C1-3 alkyl, H, C1-3 alkoxy, and C1-3 haloalkyl;R5is a 5-membered heteroaryl, optionally substituted with C1-6 alkyl or C3-6 cycloalkyl;R7is individually F or CH3, and n is 0, 1 or 2; or n is 2 and the two R7are -CH2-, and the two R7are linked together to form a ring together with the intervening atom(s);R3is phenyl optionally substituted with 1 to 4 substituents individually selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN, or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein at least one X1and X2is N, or a pharmaceutically acceptable salt thereof.

3. The compound according to any one of the preceding claims, wherein R1is a cyclic group optionally substituted with one or more, identical or different, R14, wherein the cyclic group is selected from the group consisting of phenyl, 6- membered heteroaryl, and 5-membered heteroaryl; andR14is individually selected from the group consisting of C1-3 alkyl optionally substituted with =0, N(CH3)2, and / or 1 to 3 halogens; C3-5 cycloalkyl; C1-3 alkoxy; CN; =0; and halogen, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of the preceding claims, wherein R1is phenyl optionally substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 3, wherein R1is pyridinyl optionally substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 3, wherein R1is a 5- membered heteroaryl optionally substituted with one or more, identical or different, R14, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 3 or 6, wherein the 5- membered heteroaryl is pyrazolyl, oxazolyl or isoxazolyl, or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of the preceding claims, wherein R14is individually selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, CN and halogen, or a pharmaceutically acceptable salt thereof.

9. The compound according to any one of claims 1 to 3, wherein R1is selectedpharmaceutically acceptable salt thereof.

10. The compound according to any one of the preceding claims, wherein n is 0, or a pharmaceutically acceptable salt thereof.11 . The compound according to any one of the preceding claims, wherein R5is of Formula (XII):Formula (XII) whereinR8is C1-3 alkyl, C3-6 cycloalkyl or H, or a pharmaceutically acceptable salt thereof.

12. The compound according to any one of the preceding claims, wherein R5isor a pharmaceutically acceptable salt thereof.

13. The compound according to any one of the preceding claims, wherein R2ispharmaceutically acceptable salt thereof.

14. The compound according to any one of claims 1 to 12, wherein R2ispharmaceutically acceptable salt thereof.

15. The compound according to any one of the preceding claims, wherein R3is phenyl substituted with 1 to 3 substituents independently selected from the group consisting of halogen, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and CN.

16. The compound according to any one of the preceding claims, wherein R3is selected from the group consisting of:pharmaceutically acceptable salt thereof.

17. The compound according to any one of the preceding claims, wherein R3is:thereof.

18. The compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of: 2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(2-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(3-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(4-methoxyphenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(o- tolyl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-2-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-3-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (pyridin-4-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(isoxazol-4-yl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-4-yl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- (oxazol-2-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(1- methyl-1 H-pyrazol-5-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(1-methyl-1 H-pyrazol-3-yl)-6-(2-(1-methyl-1 H- pyrazol-4-yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-N-(4-cyanophenyl)-6-(2-(1-methyl-1 H-pyrazol-4- yl)morpholino)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N-(3- methylpyridin-4-yl)pyrimidine-4-carboxamide;2-(4-chloro-2-fluorophenyl)-6-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylisonicotinamide;6-(4-chloro-2-fluorophenyl)-4-(2-(1-methyl-1 H-pyrazol-4-yl)morpholino)-N- phenylpicolinamide; and 2-(4-chloro-2-fluorophenyl)-6-(4-ethyl-3-(1-methyl-1 H-pyrazol-4-yl)piperazin-1- yl)-N-phenylpyrimidine-4-carboxamide, or a pharmaceutically acceptable salt thereof.

19. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the compound is a TREM2 modulator, such as a TREM2 activator, such as a TREM2 agonist.

20. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

21. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use as a medicament.

22. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in the treatment of a condition associated with a loss of function of TREM2, such as for use in the treatment of a condition associated with a mutation of TREM2.

23. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in the treatment of a neurodegenerative disease.

24. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in the treatment of a neurodegenerative disease selected from the group consisting of a tauopathy, a TDP-43 proteinopathy, a synucleinopathy, dementia, amyloidosis, a demyelinating disorder of the CNS, a demyelinating disorder of the PNS, a Leukoencephalopathy, a leukodystrophy, a transmissible spongiform encephalopathy (TSE) and a lysosomal storage disorder (LSD).

25. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in the treatment of a neurodegenerative disease selected from thegroup consisting of Alzheimer’s disease, Frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), Parkinson’s disease, Nasu-Hakola disease, FTLD-like syndrome, Huntington disease, Amyotrophic lateral sclerosis, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathies, Charcot-Marie-Tooth disease, prion disease, stroke, and traumatic brain injuries (TBI).

26. The compound according to any one of claims to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use in the treatment of a disease selected from the group consisting of arthritis, rheumatoid arthritis, pyle disease, osteoporosis, osteopetrosis, osteosclerosis, skeletal dysplasia, dysosteoplasia, autism spectrum disorders, autism and Aspergers syndrome, traumatic brain injuries (TBI), spinal cord injuries, muscular dystrophy, myotonic dystrophy, inclusion-body myositis, systemic lupus erythematosus (SLE), RA, gout, bowel conditions, Inflammatory bowel disease (IBD), metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic and non-alcoholic fatty liver disease, alcoholic and non-alcoholic steatohepatitis, Amyloidosis.

27. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use according to any one of claims 21 to 26, wherein said compound is administered in an amount of about 0.01 mg / kg to about 100 mg / kg bodyweight / day.

28. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, for use according to any one of claims 21 to 27, wherein said compound is administered via enteral delivery, oral delivery, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery.

29. A method for treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease, said method comprising administering a therapeutically effective amount of a compound according to any one of claim 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 20, to a subject in need thereof.

30. Use of a compound according to any one of claim 1 to 19, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim20, for the manufacture of a medicament for the treatment of a condition associated with a loss of function of TREM2, such as a neurodegenerative disease.31 . A method of enhancing or increasing TREM2 activity, such as a method of one or more of i) enhancing or activating TREM2 signaling through DAP12, ii) inducing phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex, such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT and GSK3b, iii) enhancing TREM2-induced phosphorylation levels of the Syk kinase, Iv) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes, and / or v) increasing the expression levels, such as brain expression levels, of one or more TREM2 regulated genes selected from the group consisting of CXCL10, CCL2, CST7 and TMEM119; in a subject in need thereof, such as in a subject having a neurodegenerative disease, said method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, according to any one of claim 1 to 19.

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